Experientia supplementum (2012)最新文献

Immunotoxicology is the study of undesired modulation of the immune system by extrinsic factors. Toxicological assessments have demonstrated that the immune system is a target following exposure to a diverse group of xenobiotics including ultraviolet radiation, chemical pollutants, therapeutics, and recreational drugs. There is a well-established cause and effect relationship between suppression of the immune response and reduced resistance to infections and certain types of neoplasia. In humans, mild-to-moderate suppression of the immune response is linked to reduced resistance to common community-acquired infections, whereas opportunistic infections, which are very rare in the general population, are common in individuals with severe suppression. Xenobiotic exposure may also result in unintended stimulation of immune function. Although a cause and effect relationship between unintended stimulation of the immune response and adverse consequences has yet to be established, evidence does suggest that hypersensitivity, autoimmunity, and pathological inflammation may be exacerbated in susceptible populations exposed to certain xenobiotics. Xenobiotics can act as allergens and elicit hypersensitivity responses, or they can modulate hypersensitivity responses to other allergens such as pollen or dust mite by acting as adjuvants, enhancing the development or expression of hypersensitivity. Allergic contact dermatitis, allergic rhinitis, and asthma are the most commonly encountered types of hypersensitivity reactions resulting from chemical exposure. The immunologic effectors and mechanisms involved in autoimmune reactions are the same as those associated with responses to foreign antigens; however, the reactions are directed against the host's own cells. Thus, chemicals that induce immune suppression, nonspecific immunostimulation, or hypersensitivity may also impact autoimmunity. Risk assessment for immunotoxicity should be performed using the same approaches and principles for other noncancer effects. However, since xenobiotics may have effects on more than one aspect of immune function, immunotoxicity data should be evaluated separately for evidence of suppression, stimulation, hypersensitivity, and autoimmunity.

Matrix metalloproteinases (MMPs), an increasing family of zinc- and calcium-dependent endopeptidases, are involved in both the tissue remodeling and the degradation of extracellular matrix (ECM). These enzymes have been a pharmaceutical target for over 25 years in order to develop many families of therapeutically important synthetic matrix metalloproteinase inhibitors (MMPIs) for the treatment of several serious pathologies. Although clinical trials on most of the MMPIs gave disappointing results, at least one MMPI (Periostat) has been approved by the FDA for the treatment of periodontal disease. Current research efforts on the development of selective inhibitors toward certain MMPs gave a vast number of small molecules as potent MMPIs, of which, some of the effective candidates are in their various stages of (pre)clinical trials for the treatment of various diseases such as arthritis and different cancers. The selectivity of MMPIs toward specific MMPs depends mainly on their structural templates or scaffolds and the variations in their substituents. Thus, the combination of traditional, mechanism-based, and structural-based approaches may help for the future development of specific MMPIs. In recent years, research focuses on the design and development of MMPIs possess a hydroxamic acid moiety, a strong Zn(II)-binding group, which leads to their high-affinity binding to the enzymic sites of the MMPs. We herein discuss the hydroxamic acid-based MMPIs with respect to their mechanism of interaction, structure-activity relationship (SAR), quantitative structure-activity relationship (QSAR), recent development, and clinical trials.

Most of the experimental toxicity testing data for chemicals are generated through the use of laboratory animals, namely, rodents such as rats and mice or other species. Interspecies extrapolation is needed to nullify the differences between species so as to use such data for human health/risk assessment. Thus, understanding of interspecies differences is important in extrapolating the laboratory results to humans and conducting human risk assessments based on current credible scientific knowledge. Major causes of interspecies differences in anatomy and physiology, toxicokinetics, injury repair, molecular receptors, and signal transduction pathways responsible for variations in responses to toxic chemicals are outlined. In the risk assessment process, uncertainty associated with data gaps in our knowledge is reflected by application of uncertainty factors for interspecies differences. Refinement of the risk assessment methods is the ultimate goal as we strive to realistically evaluate the impact of toxic chemicals on human populations. Using specific examples from current risk assessment practice, this chapter illustrates the integration of interspecies differences in evaluation of individual chemicals and chemical mixtures.

Quantitative cheminformatics approaches such as QSAR modeling find growing applications in chemical risk assessment. Traditional methods rely on the use of calculated chemical descriptors of molecules and relatively small training sets. However, in recent years, there is a trend toward the increased use of in vitro biological testing approaches to reduce both the length of experimental studies and the animal use for chemical risk assessment. Furthermore, there is also much greater emphasis on model validation using external datasets to enable the reliable use of computational models as part of regulatory decision making. In this chapter, recent trends emphasizing the need for both careful curation of experimental data prior to model development and rigorous model validation are investigated. Furthermore, recent approaches to chemical toxicity prediction that employ both chemical descriptors and in vitro screening data for developing novel hybrid chemical/biological models are being reviewed. Examples of respective application studies that employ novel workflows for model developments are described and recent important efforts by several academic, nonprofit, and industrial groups to start placing both data and, especially, models in the public domain are discussed.

Over the last 30 years, the field of biomarkers has greatly expanded as early and specific endpoints for monitoring cellular responses to various disease states and exposures to drugs and chemical agents. They have enjoyed some success as predictors of health outcomes for a number of clinical diseases, but the application to chemical exposure risk assessments has been more limited. Biomarkers may be classified into categories of markers of exposure, effect, and susceptibility. Currently, "omics" biomarkers (i.e., genomic, proteomic, and metabolomic/metabonomic) are the major classes of biomarkers under development. These markers represent a continuum of cellular responses to drug or chemical exposures and provide linkages to mechanisms of cell injury/cell death or carcinogenic transformation. On the other hand, translation and application of these biomarkers for risk assessment has been limited due to validation and interpretation issues that need to be addressed in order for these potentially extremely valuable endpoints to reach their full potential as predictive tools for public health. This short chapter will briefly review these three "omics" biomarker classes and examine some validation/translation aspects needed in order for them to reach their full potential and acceptance as valuable tools for application to risk assessment.

It is becoming increasingly clear that inhalation exposure to particulate matter (PM) can lead to or exacerbate various diseases, which are not limited to the lung but extend to the cardiovascular system and possibly other organs and tissues. Epidemiological studies have provided strong evidence for associations with chronic obstructive pulmonary disease (COPD), asthma, bronchitis and cardiovascular disease, while the evidence for a link with lung cancer is less strong. Novel research has provided first hints that exposure to PM might lead to diabetes and central nervous system (CNS) pathology. In the current review, an overview is presented of the toxicological basis for adverse health effects that have been linked to PM inhalation. Oxidative stress and inflammation are discussed as central processes driving adverse effects; in addition, profibrotic and allergic processes are implicated in PM-related diseases. Effects of PM on key cell types considered as regulators of inflammatory, fibrotic and allergic mechanisms are described.

The use of hazardous chemicals in organisations represents a substantial risk to occupational health, safety and the environment (OHSE). Organisational directors and managers have a responsibility to provide and maintain organisational management systems that manage these risks. The risk management approach of establishing organisational considerations, identifying chemical hazards (health and environmental), assessing and controlling risks and evaluating management activities has become the de facto means of managing organisational hazards in general and may be satisfactorily applied to the management of chemicals in the organisation. The Globally Harmonized System for the Classification and Labelling of Chemicals (GHS) is now at the forefront of major regulatory issues facing the chemicals manufacturing industry and downstream users of chemicals. The GHS offers one system for the classification of all dangerous, toxic and environmental (ecotoxic) effects of chemicals. Organisations should develop occupational health, safety and environment (OHSE) management systems which contain programs and procedures that contain systems for inventory control, hazard communication, competency training, risk assessment and control, transport and storage, monitoring and health surveillance, chemical emergencies (including accident investigation), waste minimisation and disposal, record keeping and management system review.

Perfluorinated compounds such as the perfluoroalkyl acids (PFAAs) and their derivatives are important man-made chemicals that have wide consumer and industrial applications. They are relatively contemporary chemicals, being in use only since the 1950s and until recently have been considered as biologically inactive. However, during the past decade, their global distribution, environmental persistence, presence in humans and wildlife, and adverse health effects in laboratory animals have come to light, generating scientific, regulatory, and public interest on an international scale. This chapter will provide a brief overview of recent advances in understanding environmental and human exposure, toxicology, and modes of action for this class of compounds in animal models, as well as a summary of epidemiological findings to date.

Heavy metals are naturally occurring elements that have a high atomic weight and a density at least five times greater than that of water. Their multiple industrial, domestic, agricultural, medical, and technological applications have led to their wide distribution in the environment, raising concerns over their potential effects on human health and the environment. Their toxicity depends on several factors including the dose, route of exposure, and chemical species, as well as the age, gender, genetics, and nutritional status of exposed individuals. Because of their high degree of toxicity, arsenic, cadmium, chromium, lead, and mercury rank among the priority metals that are of public health significance. These metallic elements are considered systemic toxicants that are known to induce multiple organ damage, even at lower levels of exposure. They are also classified as human carcinogens (known or probable) according to the US Environmental Protection Agency and the International Agency for Research on Cancer. This review provides an analysis of their environmental occurrence, production and use, potential for human exposure, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity.

Remodeling of extracellular matrix is crucial for many physiological (cell migration, proliferation, growth, and development) and pathological (remodeling of heart, carcinogenesis, metastasis, etc.) events. Thus, the interaction between cells and extracellular matrix plays a key role in normal development and differentiation of organism and many pathological states as well. Changes in extracellular matrix are regulated by a system of proteolytic enzymes that are responsible for proteolysis of huge quantity of extracellular matrix components. Matrix metalloproteinases (MMPs) represent the main group of regulating proteases in ECM. Ability of matrix metalloproteinases to modify the structural integrity of tissues is essential for certain aspects of normal physiology and pathology. The ability to process molecules such as growth factors, receptors, adhesion molecules, other proteinases, and proteinase inhibitors makes MMPs potent controllers of physiological and pathological events in the cell microenvironment. Overactivation of MMPs has been implicated in numerous disease states.