br Toxicity assessment in humans Toxicity

Toxicity assessment in humans Toxicity assessment in humans involves different fields such as clinical, forensic, environmental, and regulatory toxicology. A systemic determination of toxicants in body tissues is usually obtained by biopsy or by analyzing body fluids such as blood and urine. Clinical toxicology is mainly based on analyzing genotoxicity, neurotoxicity, cardiotoxicity, hepatotoxicity, nephrotoxicity, carcinogenicity, immunotoxicity, food allergy, and/or endocrine disruption as they affect a variety of disorders [13,14,16–23]. A great deal of knowledge on toxicity in humans has been obtained by post mortem molecular and anatomic analysis of cells, tissues and organs [159,160]. Forensic toxicology is very related to toxicologic pathology but focusing more on the application to the purposes of the law [160,161]. The discipline of environmental toxicology is related to studies of various chemical, biological and physical agents which are harmful to humans, whereas regulatory toxicology is concerned with risk assessment of food and potential toxicants [51,162]. By virtue of advances in nanotechnology and its application in food industry, the newly created discipline of nanotoxicology investigates safety or potential hazards of nanoparticles [52,163–165]. Another dimension refers to genetically modified organisms (GMO) or genetically modified food (GMF) as potential source of toxicity [52,166,167]. All the different disciplines of toxicity assessment in humans are not mutually exclusive but rather highly interconnected. The goal is to identify and understand the molecular mechanisms of toxicants causing adverse effects in order to ultimately prevent their intake thus increasing food safety [52,168]. A major tool in clinical toxicology is the use of surrogate biomarker molecules as specific indicators of organ and tissue damage. As a consequence of the rapid development in biotechnology an increase of specificity as well as sensitivity of detection levels has led to a better predictivity of those biomarkers. Toxicological assessment of organ and tissue damage can be grouped in two basic types of biomarkers which indicate different adverse biological effects: (1) biomarkers assessing function and integrity of buy PX-478 2HCl and tissues which are typically tissue-specific cytoplasmic enzymes that leak from damaged or dying cells and can be monitored in blood or urine. Usually, a comprehensive clinical chemistry profile is performed employing a variety of tissue-specific biomarkers as indicators for organ-specific damage such as liver, kidney, brain, heart, vascular system and muscles (Table 1) and (2) biomarkers as indicators of damage responses of cells and tissues based on the inducible cellular defense systems. Representative members for the group of inducible biomarkers such as antioxidant enzymes, antioxidants, metal-chelating proteins, repair enzymes, transcription factors, inflammatory factors or xenobiotic factors are listed in Table 2. Integration of data obtained by these two approaches as first line of toxicity assessment is usually validated by histology which may potentially lead to causative relationships relevant to degenerative diseases [3,169–173]. As a result of recent developments in metabolomics the clinical chemistry profile is enhanced by NMR technology to identify intermediary metabolites associated with a variety of pathologies and functional alterations, including renal and hepatic toxicity [170,171,174]. Furthermore, modern non-invasive techniques such as positron emission tomography (PET), fluorescence magnetic resonance imaging (fMRI), computerized tomography (CT), or single-photon emission computed tomography (SPECT) are increasingly proposed for monitoring molecular biomarkers because of possibilities for relatively direct clinical translation [6,169–171,175–177].
The integration of food toxicology data obtained throughout biochemical and cell-based in vitro, animal in vivo and human clinical settings enabled the establishment of alternative, highly predictable in silico models employing new focused cell-based bioassays as valuable tool for toxicity risk assessment in food. In silico models are being used to study pathways of subsequent cellular events, starting from a molecular initiating event, through a sequential series of higher order effects using complex in vitro cell-based models and computer algorithms [7,33,34,178]. As a basic principle, quantitative structure–activity relationships (QSAR) between a chemical structure and the biological effects give valuable insights into the molecular mechanisms of action of toxic substances. The predictive value of QSARs can be greatly enhanced by quantitative in vitro to in vivo extrapolation when toxicokinetic data on xenobiotic biotransformation, chemical–chemical interactions, absorption, distribution, bioavailability, metabolism and/or excretion of the substance under study are available [2,7,32,34,172,179,180]. Advances of these in silico tools to assess toxicity in food has led to a wealth of mechanistic information of adverse effects of food toxicants and a significant reduction in the number of animals required for toxicological tests for a new active substance [5–8,27,33]. Therefore, in silico models are being increasingly recognized as predictive tools to analyze hepatotoxicity, cardiotoxicity and nephrotoxicity [9,33,34,39,172,181–183].