Application of a key events dose-response analysis to nutrients: a case study with vitamin A (retinol).
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.
Ross
A Catharine
AC
Department of Nutritional Sciences, Pennsylvania State University, University Park, PA, USA.
Russell
Robert M
RM
Miller
Sanford A
SA
Munro
Ian C
IC
Rodricks
Joseph V
JV
Yetley
Elizabeth A
EA
Julien
Elizabeth
E
D000465:Algorithms; D062787:Drug Overdose; D006706:Homeostasis; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D014801:Vitamin A / Q000008:administration & dosage* / Q000009:adverse effects* / Q000378:metabolism; D014802:Vitamin A Deficiency / Q000378:metabolism*
D014801:Vitamin A
J Nutr. 1991 Jul;121(7):1016-25
2051220
J Biol Chem. 1994 Sep 2;269(35):22334-9
8071361
J Nutr. 2002 Dec;132(12):3616-22
12468597
Toxicol Pathol. 2002 Jan-Feb;30(1):41-53
11890475
J Nutr. 2006 Feb;136(2):493S-501S
16424134
J Nutr. 2002 Feb;132(2):197-203
11823578
Annu Rev Nutr. 1995;15:111-32
8527214
J Biol Chem. 1991 Sep 5;266(25):16453-7
1885578
Eur J Neurosci. 2003 Aug;18(3):457-72
12911743
Vitam Horm. 1995;51:403-57
7483329
J Nutr. 2001 Dec;131(12):3197-203
11739865
Annu Rev Nutr. 2002;22:347-81
12055350
J Nutr. 1998 Feb;128(2 Suppl):455S-458S
9478047
Annu Rev Nutr. 2005;25:87-103
16011460
Am J Clin Nutr. 2005 Apr;81(4):851-8
15817863
FASEB J. 1991 Nov;5(14):2924-33
1661245
J Nutr. 2008 Oct;138(10):1987S-1991S
18806112
J Lipid Res. 1995 Jun;36(6):1264-73
7666004
Toxicol Lett. 2008 Aug 15;180(2):123-30
18586418
J Lipid Res. 2005 Jul;46(7):1502-11
15834126
J Biol Chem. 2005 Sep 23;280(38):32565-8
16076839
Biochim Biophys Acta. 1993 Apr 7;1167(2):159-64
8466944
Leuk Lymphoma. 1996 Nov;23(5-6):437-42
9031073
Int J Biochem Cell Biol. 2005 Aug;37(8):1696-708
15869897
J Biol Chem. 1988 Dec 15;263(35):18693-701
3198596
Science. 2007 Feb 9;315(5813):820-5
17255476
Arch Biochem Biophys. 2002 May 15;401(2):235-43
12054474
J Nutr. 1998 Oct;128(10):1767-73
9772148
Biochim Biophys Acta. 1987 Dec 14;922(3):247-58
3689810
J Biol Chem. 2005 Oct 21;280(42):35647-57
16115871
J Nutr. 1994 Dec;124(12):2477-85
16856330
Am J Clin Nutr. 1989 Jan;49(1):112-20
2911996
N Engl J Med. 1976 Apr 8;294(15):805-8
943041
J Natl Cancer Inst. 1984 Dec;73(6):1439-44
6439934
J Chromatogr B Biomed Sci Appl. 2001 Feb 25;751(2):265-75
11236082
Crit Rev Food Sci Nutr. 2009 Sep;49(8):682-9
19690994
Nat Genet. 2002 May;31(1):7-8
11953747
J Nutr. 1994 Aug;124(8 Suppl):1467S-1472S
8064405
Liver Int. 2006 Mar;26(2):182-6
16448456
J Nutr. 2008 May;138(5):971-7
18424609
Biochim Biophys Acta. 2005 Oct 15;1737(1):76-82
16214399
Life Sci. 1996;59(12):PL169-77
8809215
J Nutr. 2004 Jan;134(1):269S-275S
14704332
J Nutr. 2000 May;130(5):1280-6
10801930
Arch Biochem Biophys. 1992 Mar;293(2):298-304
1536565
J Lipid Res. 2006 Aug;47(8):1844-51
16685080