Application of a Key Events Dose-Response Analysis to Nutrients: A Case Study with Vitamin A (Retinol)

Abstract

The methodology used to establish tolerable upper intake levels (UL) for nutrients borrows heavily from risk assessment methods used by toxicologists. Empirical data are used to identify intake levels associated with adverse effects, and Uncertainty Factors (UF) are applied to establish ULs, which in turn inform public health decisions and standards. Use of UFs reflects lack of knowledge regarding the biological events that underlie response to the intake of a given nutrient, and also regarding the sources of variability in that response. In this paper, the Key Events Dose-Response Framework (KEDRF) is used to systematically consider the major biological steps that lead from the intake of the preformed vitamin A to excess systemic levels, and subsequently to increased risk of adverse effects. Each step is examined with regard to factors that influence whether there is progression toward the adverse effect of concern. The role of homeostatic mechanisms is discussed, along with the types of research needed to improve understanding of dose-response for vitamin A. This initial analysis illustrates the potential of the KEDRF as a useful analytical tool for integrating current knowledge regarding dose-response, generating questions that will focus future research efforts, and clarifying how improved knowledge and data could be used to reduce reliance on UFs.

Keywords:

• dose-response
• tolerable upper intake levels
• vitamin A
• retinol
• uncertainty factors
• homeostatic mechanisms

ACKNOWLEDGMENTS

This paper is one of the work products of an international group of experts convened by the International Life Sciences Institute (ILSI) Research Foundation. ILSI is a nonprofit, worldwide organization established in 1978 to advance the understanding of scientific issues relating to nutrition, food safety, toxicology, risk assessment, and the environment. The ILSI Research Foundation was established in 1984 to create a vehicle for ILSI to support research. Its risk assessment program sponsors, organizes, and participates in a wide range of activities to develop and disseminate new scientific knowledge, encourage exchange of ideas, and build consensus among scientists from academia, industry, government, and public interest groups in its efforts to improve the scientific basis of risk assessment.

Financial support for this project from the following sources is gratefully acknowledged: ILSI Research Foundation, Health Canada, Ajinomoto, Coca-Cola Company, Groupe Danone, Kellogg Company, Kraft Foods, Inc., Mars, Inc., Mead Johnson Nutritionals, Monsanto Company, Nestlé, PepsiCo, Inc., The Procter & Gamble Company, Syngenta Ltd., Flavor Extract Manufacturers Association, and Grocery Manufacturers Association. Assistance from Ms. Julie Fitzpatrick with coordination of the final preparation of these papers is also gratefully acknowledged.

Declaration of Interests : All authors declare that they have no relevant interests to disclose.

Notes

¹ Throughout this discussion, the phrase “nutrient levels” is intended to refer not only to the parent nutrient compound, but also to metabolites or other downstream effectors generated by the nutrient.

² The term “thresholded” is commonly used in the field of chemical risk assessment. It refers to a dose-response relationship that is characterized by a biological threshold and a non-linear or discontinuous dose-response curve. A biological threshold is a transition point between the highest dose that will not elicit a specified biological effect, and the lowest dose that will (see Appendix to Julien et al. 2009 for further discussion).

³ LRAT also increases in some extrahepatic tissues, such as the lungs, when vitamin A or retinoic acid are above usual levels (Ross et al., 2006). In addition, ARAT activity becomes active in liver and intestine when retinol is present in high concentrations.

⁴ With hypervitaminosis A (acute or chronic), RE may exceed retinol-RBP-TTR as the major form of circulating VA. RE may be released directly from the liver and chylomicron containing RE may not be taken up by liver. Some species are known to secrete RE from the liver in lipoproteins (Wilson et al., 1987) and this could be, in part, the case in humans. Also, some chylomicron may exchange RE with circulating lipoproteins before being cleared.

⁵ While plasma retinol levels are not a sensitive indicator of status, they have some predictive value, as epidemiological data have correlated very low levels of plasma retinol levels to certain types of disease risk (e.g., impaired growth, eye disease, mortality from infectious disease) (Underwood, 1994).

⁶ Other specific vitamin A binding proteins are present in the retina's photoreceptor cells and in retinal pigment epithelial cells.

* Currently, Scientific Consultant, Rockville MD