for detrimental effects, based upon the hair analyses for MeHg. In fact, temporal records of MeHg exposure can be determined by measuring MeHg levels at various places in the human hair shaft.
Unfortunately, not all substances are comparable to MeHg in lending themselves to use as exposure biomarkers. For example, a debate continues concerning the dose of vitamin A, as retinyl esters versus retinol, that will produce malformations in humans. Of particular interest is the discussion about what dosages of vitamin A are needed to increase the blood concentrations of retinoic acid metabolites significantly above those seen in normal pregnant women. Doses of 30,000 international units of retinyl palmitate per day administered orally did not significantly increase the concentrations of retinoic acid in nonpregnant women above those concentrations already circulating in untreated pregnant women (R.K. Miller et al. 1998). Still, for many agents (e.g., ethanol, solvents, and retinoids) that cause developmental toxicity at or near adult toxic dosages, one might be able to monitor concentrations of the compound (or metabolites) in the exposed individual and thereby establish possible risk. Thus, biomarkers of exposure have the potential to be critical in establishing potential risk at a sensitive period during development.
For developmental toxicants that can produce developmental defects at dosages or concentrations not causing identifiable immediate adult toxicity (e.g., thalidomide and cigarette smoking), biomarkers of exposure that reveal actual concentrations of parent compounds or metabolites (e.g., cotinine as a nicotine-metabolite measure of cigarettes smoked) might be the only available indicators of risk.
It is believed that subtle changes in gene expression, as assayed by large-scale microassay analyses, are good examples of newly developing biomarkers of exposure. Those biomarkers still need to relate expression changes with early biological effects, occurring well before toxicity. In fact, there are extensive discussions to determine if these are truly “biomarkers of exposure” or “biomarkers of effect.” Current efforts are under way to improve the detection of differences in patterns of gene expression for various chemical classes (e.g., peroxisomal proliferators and oxidants), with the aim of improving use of patterns rather than single changes as exposure biomarkers. In cases in which maternal toxic effects occur, the patterns of expression changes might be especially useful biomarkers to improve detection of developmental versus maternal toxicity.
Biomarkers of exposure often are used in occupational and molecular epidemiology. Aniline-hemoglobin adducts, benzo[a]pyrene-DNA adducts, aflatoxin B1-DNA adducts, elevated metallothionein, and elevated urinary 8-hydroxy-deoxyguanosine levels have been useful biomarkers for specific exposures. The cancer risk of exposure to dangerous concentrations of foreign or endogenous chemicals is assessed by the activation of a proto-oncogene or the inactivation of a tumor-suppressor gene (e.g., p53), reflecting the mutation of these genes in