Nutrients are bioactive substances classified as either macronutrients (energy-producing substances—carbohydrates, fats, and proteins), or micronutrients (vitamins, minerals, and electrolytes). While the various nutrients are required for normal growth, maintenance, and repair of tissue, excess nutrient intake can cause adverse effects. Thus, considerable effort has gone toward identifying “safe” nutrient intake levels. For micronutrients, the methods for setting “tolerable upper intake levels” or “safe upper levels” have borrowed from risk assessment methodologies used by toxicologists for environmental chemicals, in which data from experimental, observational, and clinical studies are used to identify both the nature of effects resulting from excess intake and the intake levels associated with such effects (Food and Nutrition Board, 1998
; Institute of Medicine 2006
; World Health Organization/Food and Agriculture Organization of the United Nations, 2006
; Taylor and Yetley, 2008
; FSA, 2003
; SCF, 2006
As is the case with many environmental chemicals, the lowest nutrient intake level associated with an adverse effect is generally considered to represent a “threshold” level, such that any intake at or above that threshold level is expected to pose a health risk (with the specific nature of the risk being dependent on the type of nutrient and the actual intake level). To account for differences, for example, between experimental species and humans or among individual humans, Uncertainty Factors (UF) are applied to the empirically-observed threshold levels to generate reference values of use for various public health purposes. Efforts to establish such values are not as robust or refined as would be desired, due to significant data deficiencies for many substances and also due to various methodological issues, particularly relating to the ability to select appropriate UFs (Renwick and Walker, 2008
; Renwick 2006
Nutrients differ from environmental chemicals in that adverse effects may result from either inadequate intake (of an essential nutrient), or excess intake (of most nutrients). Thus, for many nutrients, two threshold levels are presumed to exist: 1) an intake level that must occur on a regular basis to prevent the adverse effects of deficiency, and 2) an intake level that must be exceeded on a regular basis for a toxic effect to occur. Between these two thresholds, there is a range of safe and sufficient nutrient intake levels.
Nutritional scientists have evaluated, on a nutrient by nutrient basis, available data and have identified values associated with such upper and lower thresholds. For example, in North America, the Institute of Medicine (IOM) is charged with identifying Dietary Reference Intake values (DRIs), which are used for a variety of purposes (e.g., food and nutrition programs and public policies, research design and evaluation, population monitoring, patient counseling, etc.). DRIs are a set of nutrient-based reference values for intakes, established for specified life-stage groups. They include the Estimated Average Requirement, defined as the value at which 50% of the population will have sufficient intake; the Recommended Dietary Allowance (RDA), defined as a level that will cover the needs of essentially all individuals; and the Tolerable Upper Intake Level (UL), the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals (Institute of Medicine, 2006
Nutrient intake levels typically vary over time and, on any given day, may fall short of RDAs or go above ULs. But various physiological homeostatic mechanisms exist to maintain systemic and cellular nutrient levels within a safe and adequate range.1
These mechanisms provide stability to the organism, and allow the body to adjust to the intake of a wide variety of foods, differing in nutrient contents, as present in most human diets. Homeostatic mechanisms also allow for adjustments to normal physiological states, such as pregnancy. However, homeostatic mechanisms may be inadequate or overwhelmed. These mechanisms cannot compensate when long-term nutrient intake is very low. Conversely, when long-term nutrient intake is very high, homeostatic mechanisms may become “saturated,” or they may become undermined by altered pathophysiological states (e.g., certain disease states, drug actions etc.). When homeostatic mechanisms fail, adverse effects (nutrient deficiency or toxicity) may ultimately result.
As explained in the introductory paper of this series (Julien et al., 2009
), a systematic analysis of individual Key Events along the mode-of-action pathway between intake and effect of concern may contribute new insight with regard to dose-response, biological thresholds, and safe intake levels. The “Key Events Dose-Response Framework” (KEDRF) provides an organizing structure for such an analysis whereby each Key Event is considered with regard to its fundamental biology (including the dose-response relationship for the individual event), and with regard to its influence on the overall dose-response relationship for the effect of concern. , reproduced from the first paper in this series, illustrates this conceptual framework.
Figure 1. Schematic of the Key Events Dose-Response Framework. The Key Events Dose-Response Framework organizes information on the multiple biological events that occur between an initial dose and the specified effect of concern. Events are indicated generically; (more ...)
As shown in , various mechanisms (e.g., homeostatic mechanisms, repair, adaptive, immune) may engage at individual events to maintain a normal physiological environment, and thereby influence the outcome of the event. Thus, the capacity of such mechanisms to maintain the environment within a normal homeostatic range (HR) will likely influence the overall dose-response relationship. Events with such mechanisms may be considered to be “control points” in the overall pathway. While every event in the pathway must occur in order to achieve the effect of concern, it is conceivable that a particular event could disproportionately influence its likelihood. Such an event could be hypothesized to be a “determining event” in that the outcome of this event tends to determine whether the effect of concern occurs, or not.
It is important to note that the biological interactions that occur at individual key events may be affected by a variety of factors (e.g., genetics, life stage, health status, behavioral patterns); these factors may exert their influence by modifying the effectiveness of homeostatic mechanisms. Understanding the conditions under which homeostatic control can be undermined or lost is fundamental to better characterizing the dose-response for nutrients, and fundamental to characterizing threshold values as well as the variability in their values.