somatic tissues. In this usage, the biomarker of exposure also comes close to being a biomarker of effect, insofar as mutagenesis is thought to be an important step in carcinogenesis. Still other biomarkers, such as aryl hydrocarbon hydroxylase (AHH) and CYP1A1 at high concentrations, are taken to reflect induction of the enzymes by high internal concentrations of potentially toxic agents and are used to predict whether a population or individual might be at risk for perinatal morbidity or mortality.
Biomarkers of effect at the molecular level are becoming as important as monitoring metabolites or a parent compound. Recently, Perera et al. (1998) confirmed an inverse relationship between concentrations of cotinine in plasma from newborns, a metabolite of nicotine, and birth weight and length. They also demonstrated a significant association between decreased body size at birth, body weight, and head circumference and increased concentrations of polycyclic aromatic hydrocarbon (PAH)-DNA adducts in umbilical cord blood above the median. This had previously been demonstrated for PAH-DNA adducts measured in the human placenta (Everson 1987; Everson et al. 1988). Such associations were related to cigarette smoking and environmental pollution. Those examples show that there can be a practical use of biomarkers of effect at the molecular level to assess exposure. Such measurements not only allow for epidemiological evaluations of environmental pollutants, such as cigarette smoke and air pollution, but they also allow those evaluations to help identify a subpopulation of individuals that might be at risk. Critical applications for such biomarkers in developmental toxicology are in the identification of those at risk, with hopes of reducing that risk by modifying exposure and by developing other intervention strategies to decrease the incidence of developmental defects. Other biomarkers include indicators of normal cell processes (e.g., cell proliferation that may occur at inappropriate times or at different levels of expression). Proliferation markers are often used for assessing immunological impacts where proliferation status is evaluated in the context of differentiation status. These immunological studies present similar issues to those in biomarker studies in developmental toxicology. Likewise, biomarkers of the apoptotic process (e.g., early biomarkers such as nexin, enzymatic changes in various caspase levels or types, and late biomarkers such as DNA fragmentation) can provide temporal, mechanistic biomarkers of effect that are also highly relevant for developmental toxicity assessments.
Other biomarkers of effect include increased concentrations of α-fetoprotein in amniotic fluid as indicative of neural tube defects, since delayed closure of the tube is thought to allow escape of this protein. Other biomarkers might be used in combination to enhance the collective ability to diagnosis or predict possible developmental anomalies (e.g., the triple assay of human chorionic gonadotropin, estriol, and α-fetoprotein for trisomy 21).