Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids

any extrapolation of animal data to predict human response has to take into account this possibility.

Key issues that are addressed in the data evaluation of human and animal studies are listed in Box 4-1.

Evidence of Adverse Effects in Humans

The hazard identification step involves the examination of human, animal, and in vitro published evidence addressing the likelihood of a nutrient or food component eliciting an adverse effect in humans. Decisions regarding which observed effects are adverse are based on scientific judgments. Although toxicologists must consider the possibility that many demonstrable structural or functional alterations represent adverse effects with respect to nutrients, some alterations may be considered of little or self-limiting biological importance. As noted earlier, adverse nutrient-nutrient interactions are considered in the definition of an adverse effect.

Causality

The identification of a hazard is strengthened by evidence of causality. As explained in Chapter 3, the criteria of Hill (1971) are

BOX 4-1 Development of Tolerable Upper Intake Levels (ULs)

Components of Hazard Identification

Evidence of adverse effects in humans
Causality
Relevance of experimental data
Pharmacokinetic and metabolic data
Mechanisms of toxic action
Quality and completeness of the database
Identification of distinct and highly sensitive subpopulations

Components of Dose-Response Assessment

Data selection and identification of critical endpoints
Identification of no-observed-adverse-effect level (NOAEL) (or lowest-observed-adverse-effect level [LOAEL])
Assessment of uncertainty and data on variability in response
Derivation of a UL
Characterization of the estimate and special considerations

Table of Contents

Front Matter R1-R23

Summary 1-20

1 Introduction to Dietary Reference Intakes 21-34

2 Vitamin C, Vitamin E, Selenium, and •-Carotene and Other Carotenoids: Overview, Antioxidant Definition, and Relationship to Chronic Disease 35-57

3 Vitamin C, Vitamin E, Selenium, and •-Carotene and Other Carotenoids: Methods 58-72

4 A Model for the Development of Tolerable Upper Intake Levels for Nutrients 73-94

5 Vitamin C 95-185

6 Vitamin E 186-283

7 Selenium 284-324

8 •-Carotene and Other Carotenoids 325-382

9 Uses of Dietary Reference Intakes 383-400

10 A Research Agenda 401-408

A Origin and Framework of the Development of Dietary Reference Intakes 409-412

B Acknowledgments 413-415

C Dietary Intake Data from the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994 416-431

D Dietary Intake Data from the Continuing Survey of Food Intakes by Individuals (CSFII), 1994–1996 432-437

E Canadian Dietary Intake Data, 1993, 1995 438-439

F Serum Values from the Third National Health and Nutrition Examination Survey (NHANES III), 1988–1994 440-457

G Options for Dealing with Uncertainties 458-462

H Glossary and Acronyms 463-468

I Biographical Sketches of Panel and Subcommittee Members 469-482

Index 483-506

Evidence of Adverse Effects in Humans

Causality