A biologic marker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific foreign chemical substance.
It is easy to see from those definitions that biomarkers of exposure and effect should be useful for linking early, low-dose exposures with pathogenesis and providing a platform for cross-species and cross-compound comparisons. Likewise, it is easy to see how biomarkers of susceptibility could be especially useful for assessing differences in temporal sensitivity and developing tissues and for cross-species and intraspecies comparisons.
The validity of a biomarker for risk assessment depends on a demonstration that it is highly associated with the outcome, such as in this context, a developmental defect. At present, few biomarkers meet the test. When evaluating biomarkers, one must investigate the mechanistic basis of the association between the biomarker and the adverse events and then determine the reliability of the comparison in a large and varied population for specificity, sensitivity, and reproducibility. A biomarker does not have to be the definitive end point for defining the problem, although that is preferable, but even having a tool to identify candidate individuals for more definitive testing can be helpful. For example, the maternal serum α-fetoprotein levels are useful in clinical screens for neural tube defects, but serum α-fetoprotein is not a definitive test for such defects.
Temporal considerations are important for using biomarkers for developmental toxicity. When considering the validity of a screening test, the gestational age at the time of assessment and, more important, the gestational age at the time of exposure to the toxicant must be considered. Such issues have growing importance as fetal therapeutic interventions are increasingly available for use (Miller 1991). Accessibility to the biological material of interest is temporally determined. For example, invasive (e.g., percutaneous umbilical blood sampling, PUBS) and noninvasive biomarker procedures (e.g., ultrasound and Doppler) for assessing the developmental state of the fetus have made possible the use of interventions that have revolutionized the clinical capabilities to treat the affected fetus. At the same time, physicians can now predict, based upon patterns of uterine blood flow, which pregnancies have a greater risk for a poor reproductive outcome (Jaffe 1998).
The pre-eminent example in this category is methylmercury (MeHg). Maternal hair concentrations, as well as blood concentrations, of MeHg correlate with adverse developmental outcomes in the children exposed in utero (Clarkson 1987). Different threshold exposures have been observed in the adult and fetus