ties) and other biological indicators (allostatic load, measures of immune function). The development and implementation of protocols for longitudinal assessment on diverse populations (e.g., WLS, the 1946 and 1958 British birth cohorts) are a high priority. Resolution of these measurement issues would provide a critical link toward understanding the mechanisms by which proximate and distal social influences exert their health-transforming effects. An important advance would be instrumentation to facilitate EEG assessments on large populations under diverse environmental conditions. In particular, microminiaturization of the EEG recording and data storage units would make ambulatory measurement of brain activation in response to naturally occurring stimuli a reality.

Refinement in the Operationalization of Allostatic Load

Implicit in the concept of allostasis, “achieving stability through change” (see Chapter 3), are nature-nurture interactions in which genes are regulated by environmental factors, leading in the short run to adaptation and in the long run to increased risk for disease. A problem with the original conceptualization of allostatic load and its measurement, however, is that the components were not organized and categorized with regard to what each measure represents in the cascade of events that lead from allostasis to allostatic load. A step toward improving the formulation of culmulative physiological burden (McEwen and Seeman, 1999) has utilized the notion of primary mediators leading to primary effects and then to secondary outcomes, which lead finally to tertiary outcomes that represent actual diseases.

Primary mediators are chemical messengers released as part of allostasis. The present operationalization of allostatic load (Seeman et al., 1997, in press) has four such mediators: cortisol, epinephrine, norepinephrine, and DHEA-S. These mediators are accessible and relatively easy to collect and measure from body fluids, such as saliva, urine, and blood. Other mediators could include inflammatory cytokines and insulin-like growth factors. These and other future measures viewed as primary mediators have wide influences throughout the body and are useful in predicting a variety of secondary and tertiary outcomes.

Primary effects are cellular events, like enzymes, receptors, ion channels, or structural proteins induced genomically or phosphorylated via second messenger systems, that are regulated as part of allostasis by the primary mediators. These are not presently measured as part of an operationalization of allostatic load, although it may be desirable to include them in future formulations, as they are the basis for secondary and tertiary outcomes. Primary effects are organ and tissue specific, and as a result secondary and tertiary outcomes must be described at this level. The con-



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