ent. The preferred type of adverse effect is a clinical outcome, such as evidence of mortality or serious morbidity that has been observed to occur in a few sensitive individuals as a direct result of consuming a nutrient above his or her needs. In situations in which the adverse effect is a chronic disease, it is possible to use clinical outcomes, such as total mortality, cause-specific mortality, or serious morbidity. The ideal type of study is an appropriately designed, long-term trial with multiple levels of nutrient intake.

However, for most nutrients, and particularly for those where adverse effects are related to chronic disease, trials with such endpoints are unavailable, especially dose-response trials that test multiple levels of intake. For sodium, trials with relevant clinical outcomes (e.g., fatal and nonfatal stroke, coronary heart disease, end-stage renal disease, kidney stones, or bone fractures) have not been conducted. In the absence of trials with clinical outcomes, a synthesis of evidence from available trials, observational studies, dose-response trials that link sodium to a well-accepted surrogate endpoint, and observational studies that link the chosen surrogate endpoint with specific clinical outcomes, must be used.

Blood Pressure as the Endpoint. Among the endpoints considered in the previous section, blood pressure stands apart in terms of the research database supporting its use as a biomarker for several diseases of substantial public health importance. Results from the most rigorous dose-response trials (see Appendix I) have documented a progressive, direct effect of dietary sodium intake on blood pressure in nonhypertensive and hypertensive individuals. Furthermore,