Biomarkers, lead toxicity

Lead Blood lead Biomarker to toxic effect in humans biomarker to external dose in humans Biomarker results can be used directly for estimation of human risk exposure apportionment and intervention possible... 

In conclusion, glycosylation of specific serum glycoproteins has been shown to change under different pathological conditions. Because chronic exposures to xenobiotics often lead to disease, it can be expected to find that the glycan compositions of selected glycoproteins serve as sensitive, reliable and easy to analyze biomarkers of toxic exposures. 

The consequences of lead exposure for the biosynthesis of heme have been studied for decades at times, various intermediates in the heme synthetic pathway have been used as biomarkers of exposure and effect. Indeed, in 1993, a National Research Council committee issued a report Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations that reviewed the literature on lead and the heme biosynthetic pathway in a chapter titled Biologic Markers of Lead Toxicity (NRC 1993). The reader is referred to that chapter for a full description of the issue. A brief summary and interpretation of this large body of research are presented below. 

Second, lead s kinetic behavior in vivo provides the means by which one can identify and exploit biomarkers of toxic lead exposures as well as determine the dose portion of critical dose—toxic response relationships for lead poisoning. Measurement of lead in whole blood and its relatively reliable use in determining both systemic lead exposure and the extent of toxic injury (dose—response relationships) is mainly feasible because we understand how Pb s toxicokinetic behavior in blood relates to the temporal and toxicological... 

Feksa LR, Oliveira E, Trombini T, Luchese M, Bisi S, Linden R, et al. Pyruvate kinase activity and 7 delta -aminolevulinic acid dehydratase activity as biomarkers of toxicity in workers exposed to lead. Arch Environ Contam Toxicol 2012 63(3) 453-60. 

Elucidation of some of the mechanisms of lead toxicity on the cellular and biochemical level has led to the development of several relatively sensitive biomarkers of lead exposure and toxicity, including measurements of the effects of lead on enzymes of the hematopoietic system. Lead-induced alterations in blood zinc protoporphyrin (ZPP) and erythrocyte 6-aminolevu-linic acid dehydratase (ALAD) activity have been established as relatively specific biomarkers of lead toxicity to the heme biosynthetic pathway (NRC 1993 USEPA 1986). Increases in blood ZPP occur as a result of inhibition of ferrochelatase (FC) by lead. Inhibition of ALAD by lead, which begins at a blood lead level of about 5 tg/dL (Chisolm et al. 1985 USEPA 1986), is considered to be one of the most sensitive biomarkers currently available. 

Coplanar PCBs, PCDDs, and PCDFs express Ah-receptor-mediated toxicity (Chapter 6, Section 6.2.4). Binding to the receptor leads to induction of cytochrome P4501 and a number of associated toxic effects. Again, toxic effects are related to the extent of binding to this receptor and appear to be additive, even with complex mixtures of planar polychlorinated compounds. Induction of P4501A1/2 has been widely used as the basis of a biomarker assay. Residue data can be used to estimate TEQs for dioxin (see Chapter 7, Section 7.2.4). 

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. 

Consequently, proteomics is a valuable tool for identification and validation of drug targets in early phases, the investigation of the mechanism of pharmacological drug activity and toxicity, and hence, individualized drug therapy. Use of biomarkers may lead to development of nonanimal models. 

The approaches described previously can be used to relate biomonitoring results to a reference population or to workplace exposures, but they do not evaluate the risk associated with the amount of a chemical found in the body. To do that, one needs to develop a relationship between biomarker concentration and toxic response, a relationship that is not commonly derived in standard toxicologic practice. The following sections outline methods for deriving such a relationship. The approaches include the ideal case of existing risk assessments based on biomarker-response relationships established in epidemiologic research. Lead and mercury are used as examples of cases in which exposure was quantified according to hair or blood biomarkers and dose-response associations were developed on this basis. 

The biomarkers of greatest utility for interpreting risk are those for which biomarker-toxicity relationships have been developed in humans, as in the case of lead and mercury. 

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