Biomarkers in Toxicology

Ramesh C Gupta, Ramesh C. Gupta

• Editorial: Academic Press
• Año: 2014
• ISBN:
  9780124046498
• Categoría: Technik & Maschinenbau
• Categoría: Gesundheit & Sicherheit in der Industrie

Biomarkers in Toxicology is a timely and comprehensive reference dedicated to all aspects of biomarkers that relate to chemical exposure and their effects on biological systems. This book includes both vertebrate and non-vertebrate species models for toxicological testing and development of biomarkers. Divided into several key sections, this reference volume contains chapters devoted to topics in molecular-cellular toxicology, as well as a look at the latest cutting-edge technologies used to detect biomarkers of exposure and effects. Each chapter also contains several references to the current literature and important resources for further reading. Given this comprehensive treatment, Biomarkers in Toxicology is an essential reference for all those interested in biomarkers across several scientific and biomedical fields.

• Written by international experts who have evaluated the expansive literature to provide you with one resource covering all aspects of toxicology biomarkers
• Identifies and discusses the most sensitive, accurate, unique and validated biomarkers used as indicators of exposure and effect of chemicals of different classes
• Covers special topics and applications of biomarkers, including chapters on molecular toxicology biomarkers, biomarker analysis for nanotoxicology, development of biomarkers for drug efficacy evaluation and much more

Part I

General

Outline

Chapter 1 Introduction

Chapter 2 Rodents model for toxicity testing and biomarkers

Chapter 3 Minipig models for toxicity testing and biomarkers

Chapter 4 Nonhuman primates in preclinical research

Chapter 5 Biomarkers of toxicity in zebrafish

Chapter 6 Caenorhabditis elegans as a model for biomarkers of diseases and toxicities

Chapter 7 Alternative animal toxicity testing and biomarkers

Chapter 8 Toxicokinetic-toxicodynamic modeling

Chapter 1

Introduction

Ramesh C. Gupta

Biomarkers can be broadly defined as indicators or signaling events in biological systems or samples of measurable changes at the molecular, biochemical, cellular, physiological, pathological, or behavioral levels in response to xenobiotics. In the field of toxicology, biomarkers have been classified as markers of exposure, effect, and susceptibility. Measurement of biomarkers reflects the time-course of an injury and provides information on the molecular mechanisms of toxicity. These biomarkers provide us the confidence of accurate diagnosis, prognosis, and treatment. The biomarkers of early chemical exposure can occur in concert with biomarkers of early disease detection, and that information aids in avoiding further chemical exposure and in the strategic development of a novel treatment, including personalized medicine (i.e. treating the patient, and not the disease). This chapter describes the variety of current types and uses of biomarkers in the toxicology field and introduces the rest of the book, which covers a wide range of timely topics concerning the latest information and research in toxicology biomarkers.

Keywords

biomarkers; markers of exposure; markers of effect; markers of susceptibility; microRNAs; toxicology; biomarkers

Biomarkers can be broadly defined as indicators or signaling events in biological systems or samples of measurable changes at the molecular, biochemical, cellular, physiological, pathological, or behavioral levels in response to xenobiotics. The Biomarkers Definitions Working Group of the National Institutes of Health (NIH) has defined the biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes or pharmacological responses to a therapeutic agent.” In the field of toxicology, biomarkers have been classified as markers of exposure, effect, and susceptibility. Measurement of biomarkers reflects the time-course of an injury and provides information on the molecular mechanisms of toxicity. These biomarkers provide us the confidence of accurate diagnosis, prognosis, and treatment. The biomarkers of early chemical exposure can occur in concert with biomarkers of early disease detection, and that information aids in avoiding further chemical exposure and in strategic development of a novel treatment, including personalized medicine (i.e. treating the patient, and not the disease). In essence, with the utilization of specific biomarkers, an ounce of prevention can be worth a pound of treatment.

Biomarkers are used in drug development, during preclinical and clinical trials, for efficacy and safety assessment. Safety biomarkers can be used to predict, detect, and monitor drug-induced toxicity during both preclinical studies and human clinical trials. Developing highly sensitive methods and their validation for measurement of biomarkers and understanding the resultant data are complex processes that require a great deal of time, effort, and intellectual input. Furthermore, understanding drug metabolism seems essential in some cases, as the metabolite of a drug can be used as a biomarker, and the drug and/or its metabolite has to be patented by the United States Patent Office and by a similar governmental office/agency in other countries. In the past, many drugs were developed with biomarker assays that guided their use, and this trend is likely to continue in the future for drug discovery and development. With the judicious use of biomarkers, as in evidence-based medicine, patients are most likely to benefit from select treatments and least likely to suffer from their adverse effects. On the contrary, utilization of a bad biomarker can be as harmful to a patient as a bad drug. Therefore, biomarkers need to be validated and evaluated by an accredited laboratory, which participates in a proficiency testing program, to provide a high level of confidence to both clinicians and patients.

In the toxicology field, biomarkers should be specific, accurate, sensitive, valid, biologically or clinically relevant, and easy and fast to perform in order to be useful as predictive tools for toxicity testing and surveillance and for improving quantitative estimates of exposure and dose. Therefore, biomarkers are utilized in biomonitoring data that are useful in a variety of applications, from exposure assessment to risk assessment and management.

In the early 1990s, Dr. Maria Cristina Fossi, from the University of Siena, Italy, emphasized the approach for the development and validation of nondestructive biomarkers over destructive biomarkers in the field of toxicology. She described the ideal biomarker as being: measurable in readily available tissues or biological products and obtainable in a noninvasive way; related to exposure and/or degree of harm to the organism; directly related to the mechanism of action of the contaminants; highly sensitive with techniques that require minimal quantities of sample and are easy to perform and cost effective; and suitable for different species. The development and validation of new techniques in the laboratory may provide the basis for a valuable field method. But, before a new biomarker’s application, some basic information is required, such as dose–response relationships, and biological and environmental factors, which can influence the baseline values of responses. It is important to mention that, when dealing with a biochemical or metabolic biomarker, species differences can be the biggest challenge for any toxicologist.

Biomarkers have applications in all areas of toxicology, especially in the field of pesticides, metals, mycotoxins, and drugs. In the case of veterinary toxicology, biomarkers of plant toxins deserve equal attention. Farmers, pesticide application workers, and greenhouse workers are exposed to pesticides by direct contact and their family members can be exposed via second-hand exposure. Measurement of residues of pesticides and their metabolites, and metals in urine, serves as the most accurate and reliable biomarkers of exposure in agriculture, industrial, and occupational safety and health settings. Recent evidence suggests that in utero or early life-exposure to certain pesticides, metals, and other environmental contaminants may cause neurodegenerative (Alzheimer’s, Parkinson’s, schizophrenia, Huntington’s, ALS, and others), metabolic, and cardiovascular diseases, and cancer later in life. In these diseases and many others, specific and sensitive biomarkers play important roles in early diagnosis, and this can serve as the cornerstone for timely therapeutic intervention.

Mycotoxin related toxicity, carcinogenesis, and other health ailments are encountered in man and animals around the world. In developing countries, where regulatory guidelines are not strictly followed, adverse health effects (especially reproductive and developmental effects) are devastating. In these scenarios, early biomarkers of exposure play a pivotal role in avoiding further exposure to the contaminated food/feed and thus safeguard human and animal health.

With the current knowledge of system biology, metabonomics, and various mathematical and computational/chemometric modelings, undetectable biomarkers can be discovered and these biomarkers can predict how tissues respond to toxicants and drugs and/or their metabolites, and how the tissue damage and repair processes compromise the tissue’s function. Imaging and chemometric biomarkers are of greater sensitivity and carry more information than conventional biomarkers, as they detect: (1) low levels of chemical exposure (exposure biomarker), and (2) an early tissue response (endogenous response biomarker). The priority will always be for the development of a noninvasive approach over an invasive approach, and nondestructive biomarkers over destructive biomarkers, but this may not be possible in all cases. Recently, the 2011 Joint SOT/EUROTOX-Debate proposed that “biomarkers from blood and urine will replace traditional histopathological evaluation to determine adverse responses,” identifying and comparing the strengths and limitations of histopathology with serum and urine biomarkers. Unlike histopathological techniques, blood and urine biomarkers are noninvasive, quantifiable, and of translational value. Of course, the complete replacement of histopathological biomarkers with blood and urine may not be possible in the near future, as in some instances histopathological biomarkers will still be used because of recent developments in invaluable molecular pathology techniques.

For the quest of developing the most sensitive and reliable biomarkers, integration of novel and existing biomarkers with a multidisciplinary approach appears fruitful. Furthermore, a multi-biomarkers approach seems more informative and accurate than a single biomarker approach. The latest technologies, such as microRNAs (miRNAs), have been well recognized as reliable and robust biomarkers for early detection of diseases, birth defects, pathological changes, cancer, and toxicities. Because they are stable in biofluids, such as blood, there is rapidly growing interest in using miRNAs as diagnostic, prognostic, and predictive biomarkers, and the outlook for the clinical application of miRNA discoveries is promising, especially in molecular medicine. The application of miRNAs is still very new. Soon incorporating pharmacological and toxicological targeting of miRNAs into the development of innovative therapeutic strategies will be routine. Still, more innovative biomarkers need to be developed that will be highly sensitive (biotechnology-based techniques), require minimum quantities of sample, and will promise high throughput screening.

At the recent annual meetings of the Society of Toxicology in San Francisco, CA, and San Antonio, TX, USA, the EUROTOX in Stockholm, Sweden, and International Congress of Toxicology in Seoul, South Korea, a large number of toxicologists emphasized the importance of biomarkers in health, disease, and to...