Use Of Biological Markers Research Articles

Use of biologic markers for toxic end-points in assessment of risks from exposure to chemicals.

Biologic markers are familiar tools for monitoring human absorption of, and reaction to, potentially toxic chemicals. The concept of applying biologic markers to the risk assessment process is a natural, but more recent, development and the principles remain to be fully elaborated. Biologic markers may be measurements of exposure, of effects, of genetic or induced sensitivity or of disease. The ideal biologic marker for risk assessment purposes is a quantitative measurement of a chemical, biochemical, functional or morphological change in the system that is initiated by a chemical and which results in pathologic change and overt toxicity. It follows that some understanding of the mechanism of toxicity and of dose-response relationships are pre-requisite for selection of suitable biologic markers for use in risk assessment. Where biologic markers for toxicity are common between mammalian species, extrapolation of data for quantitative risk assessment purposes becomes more reasonable. In the field of carcinogenesis, some DNA and protein adducts have been proposed as biologic markers for assessment of risk associated with exposure to genotoxic carcinogens. However, less progress is evident in relation to other toxic end-points including those for pulmonary, reproductive, immuno- and neuro-toxicity, despite intensive efforts.

Biomarkers in epidemiology: scientific issues and ethical implications.

The current generation of biologic markers have three characteristics that differentiate them from previous ones. These include the ability to detect xenobiotics at concentrations at the cellular and molecular level, to detect earlier biologic changes presumptive of disease or disease risk, and to identify a detailed continuum of events between an exposure and resultant disease. If biomarkers are to enhance cancer epidemiology, they must be valid, reliable, and practical. When these characteristics have not been previously demonstrated, pilot studies should be conducted prior to the primary study. Interdisciplinary communication and collaboration is required so that useful markers are selected and that collection and handling, assay, and interpretation are appropriate. The status of many biomarkers is that they have been developed in the laboratory but lack validation for field use. Validation of a marker for use in a population requires attention to issues of background prevalence, sample size, natural history, persistence, variability, confounding factors, and predictive value. Additionally, practical features such as subject preparation, access to specimens, specimen storage aspects, and costs must be clarified. Ultimately, the use of biologic markers in epidemiologic studies will depend on how well the markers increase ability to reduce misclassification, provide for better interpretation of exposure-disease associations, and increase opportunities for prevention. Validation studies and general research using biomarkers also have clinical, ethical, and legal implications. These range from communicating uncertainty about the meaning of a marker to the kinds of societal response that result when groups or individuals are identified as having an "abnormal" marker frequency.

Commentary: Biomarkers in Epidemiology: Scientific Issues and Ethical Implications

The current generation of biologic markers have three characteristics that differentiate them from previous ones. These include the ability to detect xenobiotics at concentrations at the cellular and molecular level, to detect earlier biologic changes presumptive of disease or disease risk, and to identify a detailed continuum of events between an exposure and resultant disease. If biomarkers are to enhance cancer epidemiology, they must be valid, reliable, and practical. When these characteristics have not been previously demonstrated, pilot studies should be conducted prior to the primary study. Interdisciplinary communication and collaboration is required so that useful markers are selected and that collection and handling, assay, and interpretation are appropriate. The status of many biomarkers is that they have been developed in the laboratory but lack validation for field use. Validation of a marker for use in a population requires attention to issues of background prevalence, sample size, natural history, persistence, variability, confounding factors, and predictive value. Additionally, practical features such as subject preparation, access to specimens, specimen storage aspects, and costs must be clarified. Ultimately, the use of biologic markers in epidemiologic studies will depend on how well the markers increase ability to reduce misclassification, provide for better interpretation of exposure-disease associations, and increase opportunities for prevention. Validation studies and general research using biomarkers also have clinical, ethical, and legal implications. These range from communicating uncertainty about the meaning of a marker to the kinds of societal response that result when groups or individuals are identified as having an abnormal marker frequency.

Environmental tobacco smoke: Medical and Legal Issues

Adequate information is available linking ETS to several medical problems, including respiratory illnesses in children and lung cancer in adults; nonetheless, continuing investigation is necessary to clarify several issues. Reliable information needs to be gathered on the quantity and fate of ETS chemicals in ordinary indoor environments; improved surveys quantifying passive smoke exposure should be tested along with the use of biologic markers to quantify exposure-dose relationships in nonsmokers. To date, legislation and private initiatives have been the most promising of the various measures to protect nonsmokers from ETS. While nonsmokers' judicial action has had variable success, it places the burden of challenging smoking on the nonsmoker, and it entails piecemeal, case-by-case resolution. On the other hand, legislation and private policies relieve the nonsmokers' burden to initiate the challenge, and they protect greater numbers of nonsmokers. Furthermore, legislation and policies may have a great number of direct and indirect effects. In the short term, legislation and policies that are adequately implemented and enforced alter the behavior of smokers in areas where smoking is prohibited and should result in a reduced concentration of tobacco smoke in those areas. In the long term, policies and legislation that restrict smoking in public places and the workplace help to reinforce nonsmoking as the normative behavior in society. Smoking restrictions increase public awareness and acceptance of health risks of tobacco smoke. The combination of altered social norms and reduced opportunities to smoke may encourage smokers to quit and nonsmokers, especially adolescents, not to start.

Assessment of exposure to pulmonary toxicants: Use of biological markers

The use of biological markers to determine the extent of prior exposures to a specific chemical and to predict future disease outcome holds great promise. Knowledge of the kinetics of formation and breakdown or clearance used to monitor exposures or to predict adverse health outcomes in a quantitative manner. Also required is more quantitative information on the relationship between the markers and resultant disease. Much of the detailed kinetic information must be obtained from animal studies. The use of PBPK modeling can help to integrate the kinetic data into a useful tool for extrapolation of data from high-to-low dose, between different exposure regimes, and from animal data to expected values in humans.

Assessment of Exposure to Pulmonary Toxicants: Use of Biological Markers

Assessment of Exposure to Pulmonary Toxicants: Use of Biological Markers Get access JAMES A. BOND, JAMES A. BOND *Chemical Industry Institute of ToxicologySix Davis Drive, P.O. Box 12137, Research Triangle Park, North Carolina 27709 Search for other works by this author on: Oxford Academic PubMed Google Scholar LANCE A. WALLACE, LANCE A. WALLACE †U.S. EPA/EPICBuilding 166, Bicher Road, Vint Hill Farm Station, Warrenton, Virginia 22186 Search for other works by this author on: Oxford Academic PubMed Google Scholar SIV OSTERMAN-GOLKAR, SIV OSTERMAN-GOLKAR ‡Chemical Industry Institute of Toxicology and Department of Radiobiology, University of StockholmS-106 91 Stockholm, Sweden Search for other works by this author on: Oxford Academic PubMed Google Scholar GEORGE W. LUCIER, GEORGE W. LUCIER §NIEHS, Division of Biometry and Risk AssessmentP.O. Box 12233, Research Triangle Park, North Carolina 27709 Search for other works by this author on: Oxford Academic PubMed Google Scholar ALAN BUCKPITT, ALAN BUCKPITT ¶Department of Pharmacology and Toxicology, University of California/Davis, School of Veterinary MedicineDavis, California 95616 Search for other works by this author on: Oxford Academic PubMed Google Scholar ROGENE F. HENDERSEN ROGENE F. HENDERSEN ‖Lovelace Inhalation Toxicology Research InstituteP.O. Box 5890, Albuquerque, New Mexico 87185 Search for other works by this author on: Oxford Academic PubMed Google Scholar Toxicological Sciences, Volume 18, Issue 2, February 1992, Pages 161–174, https://doi.org/10.1093/toxsci/18.2.161 Published: 01 February 1992 Article history Received: 23 September 1991 Accepted: 23 September 1991 Published: 01 February 1992

Genetic Classification of the SE Turkey Crude Oils and Delineation of the Source Rock Types with the Use of Biological Markers

Genetic Classification of the SE Turkey Crude Oils and Delineation of the Source Rock Types with the Use of Biological Markers

Use of biological markers and pharmacokinetics in human health risk assessment.

There are two reasons to connect discussions of biological markers and pharmacokinetics. First, both tend to open up the black box between exposure and effect. Doing this promises more complete scientific understanding than simple input-output analysis, the possibility of better mechanism-based projection of risk beyond the range of possible direct observations, and the possibility of greater sensitivity of analysis, in some cases going from the organism to the cell as the unit of analysis. Second, pharmacokinetic (or similar pharmacodynamic) analysis will often be essential for appropriate interpretation of biological marker information. One needs some sort of dynamic model of the generation and loss of the marker in relation to exposure in order to use a biological marker, either to form a better measure of dosage (either accumulated past dose, or biologically relevant dose), or to make an improved prediction of effect. (For example, the use of a blood cadmium level alone to predict kidney effects might be inferior to predictions based on aggregate past accumulation of cadmium in the kidney, based on the past history of cadmium blood levels x time). Several examples will be discussed of the use of biomarkers and pharmacokinetics in risk assessments for both carcinogenesis and other effects.

Validation of Biologic Markers for Use in Research on Chronic Fatigue Syndrome

Unresolved aspects of chronic fatigue syndrome can be addressed by research involving biologic markers. These may be any molecular, biochemical, physiological, or other biologic parameter obtainable from biologic specimens. The use of biologic markers in research requires their validation as dependent or independent variables. Additionally, other characteristics of markers such as reliability of assays, background level, confounding factors, interpretations, and legal and ethical implications should be considered before the use of markers in research. A checklist is provided for evaluating a biologic marker before its inclusion in research.

Contribution of biological markers to occupational health

Occupational diseases are now being assessed at the cellular and molecular levels; this presents new opportunities for prevention and control [Calleman et al., 1978; Ong et al., 1987; Stejskal et al., 1989; Welch and Cullen, 1988; Garry et al., 1989]. The key to these opportunities is the ability to detect biological markers that reflect exposure, response, and susceptibility. Biological markers are not new, however. Biological markers such as blood lead, urinary phenol levels in benzene exposure, and liver function assays have long been used in occupational and public health research and practice. What distinguishes the current generation of markers from previous markers is a greater degree of analytical sensitivity and the ability to describe events that occur earlier in the progression between exposure and clinical disease. There are now new domains of response that were not known to exist 20 years ago. Accompanying this sensitivity is the increased requirement to consider the numerous factors that can influence the appearance of biological markers. It has been observed that all workers with similar exposures do not develop disease or markers indicative of exposure or disease. Various acquired and hereditary host factors are responsible for this variation in responses. The role of assessing the nature and degree of variation between individuals is of paramount importance. Finally, the use of biological markers in occupational health research and practice also brings new ethical and legal considerations into high profile. This paper presents my personal opinions on how biological markers can contribute to occupational health efforts and the new requirements that they bring to the field. As with any technological change, the more we can anticipate the impact, the better our ability to adjust.

Use of Biological Markers and Pharmacokinetics in Human Health Risk Assessment

Use of Biological Markers and Pharmacokinetics in Human Health Risk Assessment

Adolescent Suicide

Suicide is a major public health problem among adolescents. Although the event is rare, and rates have stabilized and even shown slight reduction in recent years, suicide has nevertheless become the second leading cause of morbidity among youths aged 15 to 24, which is otherwise a robust and relatively disease-free population. Although research on predictive factors has yielded increasingly sensitive indices of who the high-risk adolescent might be, the inherent difficulty of predicting rare events from common ones has made sensitive and specific prediction most elusive. Current neurobiologic research holds promise for the use of biologic markers in the identification of high-risk adolescents, and pharmacologic research may yield further advances in the treatment of affectively disordered youths. At this point, the most promising approaches to treating adolescent suicide appear to be (1) treatment of disorders antecedent to suicide crises, such as depression, substance abuse, family conflict, and conduct disturbance, and (2) prevention efforts targeting known high-risk groups, such as affectively disordered young men with accompanying alcohol and drug involvement and other antisocial behavior.

New Horizons in the Use of Biological Markers

New Horizons in the Use of Biological Markers

Treatment of malignant germ cell tumors in children: Experience of the Institut Gustave Roussy and the French Society of Pediatric Oncology

Much progress has been made in the past decade in our knowledge of the treatment, pathology, and use of biological markers in malignant germ cell tumors (MGCT) in children and in adults. In France, a common prospective study on these tumors was started in 1985 by the French Society of Pediatric Oncology (SFOP). It is based primarily on the experience of the Institut Gustave Roussy (IGR) between 1978 and 1984. We report here the results concerning the patients treated in IGR between 1978 and 1984 and the preliminary results of the SFOP study.

Cancer Risk Assessment and Prevention: Where Do We Stand?

This paper reviews selected aspects of progress and setbacks in cancer risk assessment and prevention during the four decades since the founding in 1947 of the Institute of Environmental Medicine at the New York University Medical Center. The period has been marked by substantial gains in quantifying the risks posed by exposures to known human carcinogens such as tobacco and ionizing radiation. By contrast, the search for sensitive and specific laboratory screens for human carcinogens has met setbacks, and epidemiological data still are needed to monitor the adverse effects of environmental exposures. The determination of acceptable levels of exposure to potential human carcinogens remains a formidable task, one for which no scientific framework yet exists. Future challenges in cancer risk assessment include the validation and use of biological markers of exposure and effective monitoring of risk among exposed populations. Future challenges in cancer prevention include the elimination of tobacco consumption and the acquisition of knowledge needed to prevent nutritionally and hormonally related cancers such as cancers of the bowel, prostate, and breast.

Cancer risk assessment and prevention: where do we stand?

This paper reviews selected aspects of progress and setbacks in cancer risk assessment and prevention during the four decades since the founding in 1947 of the Institute of Environmental Medicine at the New York University Medical Center. The period has been marked by substantial gains in quantifying the risks posed by exposures to known human carcinogens such as tobacco and ionizing radiation. By contrast, the search for sensitive and specific laboratory screens for human carcinogens has met setbacks, and epidemiological data still are needed to monitor the adverse effects of environmental exposures. The determination of acceptable levels of exposure to potential human carcinogens remains a formidable task, one for which no scientific framework yet exists. Future challenges in cancer risk assessment include the validation and use of biological markers of exposure and effective monitoring of risk among exposed populations. Future challenges in cancer prevention include the elimination of tobacco consumption and the acquisition of knowledge needed to prevent nutritionally and hormonally related cancers such as cancers of the bowel, prostate, and breast.

Biology of Depression

Research over the past three decades has led to a greater understanding of the biologic basis of depression. Observations that certain medications could improve or worsen mood led to the development of hypotheses describing the possible role of specific neurotransmitters in the brain in depression. Modifications of these original hypotheses focused on altered receptor function, failures in the regulation of neurotransmitter systems, and interactions of the monoamines with cholinergic systems. Strategies using endocrinologic measurements in the evaluation of the depressed patient have provided researchers with new clues regarding disordered neuroendocrine function in depression and clinicians with new tests to aid in diagnosis and management. Moreover, the development of standardized sleep EEG methodology has proven useful for the identification of characteristic sleep abnormalities in depression. Although there are many methodologic and clinical problems still to be resolved, the use of biological markers in the assessment of the depressed patient is increasing, and is likely to be of significant importance in the future. Finally, recent advances in molecular genetics hold promise for further advances in our understanding of the inheritance and biochemistry of depression.

The Use of Biological Markers in Risk Assessment

The use of biologic markers (such as DNA adducts) as more proximate measures of effective dose has many potential advantages for risk assessment. We can hope for: Better modeling of dose-response relationships, by avoiding the attribution of high dose pharmacokinetic nonlinearities to the fundamental multiple mutation process of carcinogenesis. Better interspecies projection of doses and risks. Improved evaluation of past doses in epidemiologic studies. Insights into the magnitude and significance of human interindividual variability. Possibly some identification of previously unrecognized genetic hazards. In the very long run, the quantification of rates of post-initiation stages in tumor development by comparative measurements of the prevalence of adducts, premalignant foci/clones and tumors as a function of age in different tissues. Realizing these advantages will require statistically oriented professionals in risk assessment to gain familiarity with more complex, simulation-type modeling approaches with multiple points of comparison between theory and experiment--rather than the straightforward curve-fitting that has built the field to this point. It will also require some precautions to avoid mistakes and misuse of these new kinds of data and related theory.

Biological markers in epidemiologic research.

This paper identifies some of the issues relevant to the use of biological markers in epidemiologic research. Foremost among these are clarity of definitions and marker classification. Illustrations of markers in the categories of internal dose, biological effective dose, biological response, disease, and susceptibility are presented with a theoretical model for the interrelationship among these. Issues faced by epidemiologists in selecting markers for specific studies concern exposure complexity, marker specificity, marker persistence, time to appearance, and the use of target vs. surrogate biological media. Feasibility issues concern sample collection, transport, storage, and characteristics of the laboratory assay. The rationale for biological markers in epidemiologic research is strong in that markers have the potential for (1.) improving the accuracy of our "exposure variables," (2.) permitting the identification of preclinical disease and providing opportunities for prevention, (3.) allowing for more homogeneous and etiologically relevant classifications of disease, and (4.) enhancing our understanding of the biological processes leading to disease occurrence, thereby strengthening the interpretation of epidemiologic data and the theoretical framework from which we formulate research questions.

Exposure assessment: input into risk assessment.

The validity of a risk assessment can be no better than that of the exposure assessment upon which it is based. The general paucity of relevant exposure data, combined with the limited appreciation by most risk assessors of the critical dimensions and metrics of exposure, often leads to an overreliance on exposure models of questionable validity. The problems of identifying and interpreting relevant metrics of exposure for epidemiologic studies and risk assessments are illustrated through the presentation of three case studies. The first examines the effects of ozone on respiratory mechanical function and demonstrates that the appropriate averaging time is greater than or equal to 6 hr, rather than 1 hr, as is implied by the current ambient air quality standard. The second case study examines the effects of sulfur oxides and particulate matter in ambient air on morbidity and mortality. It indicates that the effects are most closely associated with the acidity of the aerosol, providing a basis for an index of exposure more relevant than those currently used, i.e., sulfur dioxide and nonspecific gravimetric mass concentration of particulate matter. The third case study examines the effects of lead on blood pressure. It shows that blood lead in concentrations below 35 micrograms/dL correlates with blood pressure in both humans and animals independently of other known causal factors for blood pressure elevation. It also examines the variable relations between levels of lead in blood and in environmental media to illustrate the potential problems which can arise from the use of biological markers, such as lead in blood, as indices of exposure.