Biomarkers feasibility

The latest consensus on the definition and management [1] of anaphylaxis agrees on the lack of imiversally accepted diagnostic criteria and reliable laboratory biomarkers to confirm the clinical impression. Sometimes it is not feasible to obtain the samples within the optimum time frame. Moreover, in spite of a correct collection of samples, histamine and/or tryptase are within normal levels. Hence, new markers should be explored and further research into the role of selected mediators is urgently needed. Recently however, studies from animal models have shown promising results. In this chapter we will seek to review our current knowledge on confirmed or putative markers for the in vitro diagnosis of anaphylaxis. 

Although the feasibility of the proteomics or bioinformatics approach has been demonstrated, considerable room remains for improved methods for selective solublization of protein biomarkers and for rapid cleavage to produce peptides. There is also demand for advanced instrumentation to collect, process, and analyze microorganisms. 

Short-term non-invasive biomarkers for processes producing long-term lung damage-evaluation of the feasibility of candidate measurement systems. Toxicokinetic models have been developed to determine whether breath analysis of pentane and ethane can be used to estimate chronic lung damage from toxicants. 

J.P. Dworzanski, W.H. McClennen, P.A. Cole, S.N. Thornton, H.L.C. Meuzelaar, N.S. Arnold and A.P. Snyder, Field-portable, automated pyrolysis-GC/IMS system for rapid biomarker detection in aerosols A feasibility study, Field Anal. Chem. Technol., 1 (1998) 295-305. 

To select and determine the amount of food colours commonly found in test foods and to develop ELISA methods using 24 hr urinary samples to examine feasibility of urinary biomarkers. 

The various organs of the immune system such as spleen, lymph nodes, thymus and bone marrow containing the cells involved in the various immune responses offer the possibility to harvest these cells and perform in vitro assays for evaluation of effects on the immune system. When part of an in vivo animal study this may indicate a direct toxic effect of pharmaceuticals, that is, immunosuppression (Table 18.2). So, it is feasible to obtain cell suspensions for further evaluation such as determination of cellular subsets of T and B leukocytes by fluorescent activated cell sorter analysis (FACS analysis), and determination of natural killer (NK) cell activity of the spleen cell population. An advantage of this approach is that it may lead to identification of a biomarker to be used in clinical studies. In addition, in vitro stimulation of spleen cells with mitogens activating specific subsets may indicate potential effects on the functionality of splenic cell populations. Concanavalin A (Con A) and phytohemagglutinin (PHA) activate Tcells, while lipopolysaccharide (LPS) activates primarily B cell populations. Blood is collected for total white blood cell (WBC) determination and blood cell differential count. In addition, serum can be obtained for determination of serum immunoglobulins. 

This study shows that assessment of ERCC 1 mRNA expression in patient tumor tissue is feasible in the clinical setting and predicts response to docetaxel plus cisplatin. Further studies are warranted to optimize methodologies for ERCCI analysis in small tumor samples and to refine a multi-biomarker profile predictive of patient outcome. Other... 

Participants in public-health studies that measure hundreds of biomarkers might give informed consent only with respect to the general objectives of the study on the grounds that detailed discussion of each biomarker is not feasible. However, failing to provide more detailed information raises ethical questions. The committee recommends research... 

It is not feasible to study a wide array of tissues in a general population sample, so it is important to identify tissues that most accurately account for the body burden of most of the chemicals of concern. Figure 4-5 shows the main routes of exposure and the matrices available for analysis of biomarkers based on the metabolism and pattern of bioaccumulation and... 

It is desirable to collect as many different matrices from each study participant as is feasible and to process them with consideration of both immediately planned analyses of biomarkers and future uses. For example, several Children s Environmental Health Centers obtained urine, peripheral blood, cord blood, breast milk, meconium, saliva, hair, placental tissue, infant formula, indoor and outdoor air, and house dust from longitudinal birth cohort studies (Eskenazi et al. 2005). The centers have analyzed concentrations of numerous compounds in those biologic and environmental samples, such as pesticides, phthalates, mercury, lead, cotinine, polycyclic aromatic hydrocarbone (PAHs), PAH-DNA adducts, allergens, endotoxin, antioxidant micronutrients, cholinesterase, and thyroid hormones. Most centers also banked samples for future analyses. 

Staessen, J.A., Nawrot, T., Hond, E.D., Thijs, L., Fagard, R., Hoppenbrouwers, K., Koppen, G., Nelen, V., Schoeters, G., Vanderschueren, D., 2001. Renal function, cytogenetic measurements and sexual development in adolescents in relation to environmental pollutants A feasibility study of biomarkers. Lancet 357, 1660-1669. 

The feasibility of using the monoester metabolites as specific biomarkers of exposure to DEHP and six other commonly used phthalates was shown in a study of urine samples collected from 289 adults during 1988-1994 as part of the Third National Health and Nutrition Examination Survey (NHANES III)... 

A recently published review [44] summarizes the importance and development of this approach. The major application is seen for the description of target site equilibration, transduction, target interaction and activation, homeostatic feedback and disease process. Especially, the search and implementation of new biomarkers makes this approach feasible and promising for the future application of PD models in clinical drug development. 

While the use of preclinical disease models offers many advantages, such as the potential for identification of biomarkers for clinical trials and a direct estimation of the therapeutic index, there are also disadvantages to this approach. The disadvantages can include a paucity of historical/baseline data and inherent variability of the model, the technical feasibility of using a particular disease model, the onset/severity of the injury in the animals as this may be different from humans, and the fact that the model may only emulate select aspects of the human pathophysiology of the disease [43], It is important to use behavioral models that have adequate sensitivity and specificity to allow for correlation with morphological and biochemical findings, as in the area of spinal cord injury. 

The presence of benzene metabolite-DNA adducts may be useful as a biomarker of exposure. DNA adducts with benzene metabolites have been found after benzene exposure (Hedli et al. 1990 Lutz and Schlatter 1977 Reddy et al. 1989a). However, the feasibility of using DNA adducts themselves as biomarkers of exposure is not clear at this time. Norpoth et al. (1988) found that degradation products of DNA adducts could be detected in the urine of rats after high-dose exposure. Assay of these degradation products may prove to be a more useful method of biomonitoring benzene exposure. 

Tissue residues alone do not convey information about biological responses to chemical exposure. Furthermore, measuring tissue residues is not feasible with chemicals that do not readily bioaccumulate, or with complex mixtures that require time and cost-intensive analyses that may not identify all toxic chemicals. In such cases, other indirect measures may be preferable for indicating a biological response to a toxicologically significant exposure (i.e., a biomarker, see below). 

Caution should be taken when applying these transcription based assays. First, the biomarkers introduced into cells may alter cell response. Second, if fluorescence biomarkers such as GFP are used, the analyte of interest should be examined for autofluoresce to determine the feasibility of using a cellular fluorescence assay for the resolution of small effects [76]. Furthermore the process of transcription and translation can introduce a time lag between exposure and observable responses. 

Chen C, Malone KE, Prunty J, Daling JR. Measurement of urinary estrogen metabolites using a monoclonal enzyme-linked immunoassay kit Assay performance and feasibility for epidemiological studies. Cancer Epidemiol Biomarkers Prev 1996 5 727-32. 

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