Biologically effective dose markers

Chelatable lead Years Involves injection and timed collection of urine represents chelatable compartment of lead found mostly in soft tissues partly in bone Biologically Effective Dose Markers... 

Figure 1 Biomarkers for risk assessment Toward the left are biomarkers of exposure (dosimetry) most of these markers represent values obtained from toxicokinetic studies. Toward the right are biological markers of effect many of these markers are standard signs and symptoms familiar to clinicians. The goal of biomarker research is to obtain more information on the link between biologically effective doses and the early, initial biological changes that can lead to disease such values will come from studies on the mechanism of disease induction.

Perhaps the most fruitful area of research for identifying biomarkers of exposure that can be linked to disease outcome is the study of mechanisms of disease induction. It is not possible to define a marker of a biologically effective dose unless the mechanism by which the biological effect is induced is known. Likewise, the earliest biological events that lead to a disease cannot be determined unless the mechanism of disease induction is understood. Mechanistic studies should help to link the biologic markers represented by traditional toxicokinetic measurements and the biologic markers represented by traditional clinical markers of disease. 

While methods for the determination of DMA adducts in humans provides information about the biologically effective dose of a carcinogen, and can therefore be used as a marker of exposure, information about the relationship of these measurements to risk is unknown. Future epidemiologic studies are needed to provide this information. 

PbB concentrations reflect the absorbed dose of lead. However, the interpretation of PbB data depends on a knowledge of the past history of exposure to lead. This is because in the body, bone constitutes the major lead sink and this results in lead having a long body half-life. Thus, in the absence of intense exposure to lead for a considerable period up to its body half-life, the PbB concentrations reflect recent lead exposures. However, if intermittent exposure to lead is occurring in several distinct environments, the PbB concentration reflects both recent and past exposures to lead. Thus, biological effects for populations with the same PbB concentrations may not be the same since different exposure times scales may be involved. This is the reason why free erythrocyte protoporphyrin (FEP) and erythrocyte zinc protoporphyrin (ZPP) have been used as additional biological markers since their elevation is more related to chronic lead exposure than acute lead exposure (see Section 2.7). 

Stability The marker for GFR measurement should be biologically inert, which implies the absence of binding to plasma proteins, reabsorption in the renal tubule, deleterious effect on renal function, and intact excretion of the filtrate in the urine without degradation. This biological inert criterion, albeit difficult to achieve synthetically, confers an enormous advantage for speedy regulatory approval, especially if small doses are used. 

The UEL for reproductive and developmental toxicity is derived by applying uncertainty factors to the NOAEL, LOAEL, or BMDL. To calculate the UEL, the selected UF is divided into the NOAEL, LOAEL, or BMDL for the critical effect in the most appropriate or sensitive mammalian species. This approach is similar to the one used to derive the acute and chronic reference doses (RfD) or Acceptable Daily Intake (ADI) except that it is specific for reproductive and developmental effects and is derived specifically for the exposure duration of concern in the human. The evaluative process uses the UEL both to avoid the connotation that it is the RfD or reference concentration (RfC) value derived by EPA or the ADI derived for food additives by the Food and Drug Administration, both of which consider all types of noncancer toxicity data. Other approaches for more quantitative dose-response evaluations can be used when sufficient data are available. When more extensive data are available (for example, on pharmacokinetics, mechanisms, or biological markers of exposure and effect), one might use more sophisticated quantitative modeling approaches (e.g., a physiologically based pharmacokinetic or pharmacodynamic model) to estimate low levels of risk. Unfortunately, the data sets required for such modeling are rare. 

A distinction is made between biomarkers and bioindicators because they can be used in quite different ways and for different purposes in a risk assessment context. As mentioned above, a biomarker is considered to be a surrogate marker of exposure or an early biological marker of effect (e.g., mutations in reporter genes, total chromosome alterations). In contrast, a biological marker of effect that is itself a key event along the pathway from a normal cell to a transformed one is described as a bioindicator (e.g., mutation in critical gene for cancer, cancer-specific chromosome translocation). Biomarkers can be used to inform the dose-response for tumors in a qualitative manner. Bioindicators can be used in a qualitative and quantitative way to inform tnmor dose-response curves. Use of these biomarkers and bioindicators can make it feasible to characterize a dose-response curve at exposure levels below those at which increases in tnmor frequency can be assessed. 

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