1. RISK ASSESSMENT: Expanding the Method and Applications
John Hathcock, Ph.D.
Council for Responsible Nutrition
(USA)

2. Who Uses Risk Assessment?
US-IOM

3. Previous Characteristics of Nutrient Risk Assessment
Vitamins and minerals only
Defined for other substances, but not done by IOM, EFSA, EVM or FAO/WHO
No UL set when no adverse effects are established
Uncertainty Factors for each dataset: to 300, including fractions

4. Previous Methodology
Identify critical effect (stop procedure if not found—no UL can be established)
Evaluate dose-response relationship to identify NOAEL or LOAEL
Judge uncertainty in dataset (select UF)
Calculate UL = NOAEL ÷ UF
Compare actual intakes with UL

5. Published Risk Assessments for Nutrients
Vitamins and Minerals
IOM, SCF-EFSA, EVM, Japan (others?),
CRN Vitamin and Mineral Safety, 1st Ed 1997, 2nd Ed 2004
IADSA Safety of Vitamins and Minerals: Safe Levels Identified by Risk Assessment, 2004
Hathcock et al Risk assessment for vitamin D (Am J Clin Nutr, Jan 2007)
Bioactives
No reviews by IOM, SCF-EFSA or EVM
IADSA Risk Assessment and Safety of Bioactive Substances in Foods (2006)
Hathcock & Shao: series of 5 peer reviewed papers in Regulatory Toxicology and Pharmacology (2006-7)
Amino Acids
No UL by IOM
No reviews by SCF-EFSA or EVM
OSL(HOI) for Arginine, Glutamine and Taurine (Shao & Hathcock, 2008)

6. Expanded Nutrient Risk Assessment
Method
Highest Observed Intake (HOI)—use when UL cannot be identified
Data selection to allow UF = 1.0
Applications
Bioactive substances in foods/supplements
Amino acids

7. Expanded Approach to UL*
Highest Observed Intake (HOI) defined by FAO/WHO (OSL by CRN/IADSA) will allow risk assessment where no UL can be identified
Will support risk management decisions based on RA
Allows RA for Bioactives and Amino Acids
Several peer-reviewed papers and IADSA document
Data selected conservatively to allow UF = 1.0
Avoids quantitatively arbitrary UF values
Peer-reviewed example: Vitamin D (Hathcock et al, Am J Clin Nutr, 2007)
Can be used with HOI or for UL
*John N. Hathcock and Andrew Shao J. Nutr. 138: 1992S–1995S, 2008

8. Expanded Methodology: No Established Toxicity:
Highest Observed Intake (FAO-WHO Report)
--- the highest intake level with sufficient and appropriate evidence to conclude absence of toxicity within observed range of intake—can be identified even if no established adverse effects at any level
--- Previously termed Observed Safe Level (OSL) by CRN and IADSA
An extension of the UL method—not a replacement
--- if a NOAEL or LOAEL can be identified, a UL should be set

9. IOM—Arbitrary UF Selections?
Nutrient UF
Data type
Rationale
Vitamin E 36
Animal LOAEL
Species different
Folic acid 5
Human LOAEL
No NOAEL
Vitamin B6 2
Human NOAEL
Small, uncontrolled CTs
Iron
1.5
Large dataset
Nicotinic acid
Transient, not-toxic effect (flushing)
Fluoride
1.0
LOAEL is a cosmetic effect (mottling of teeth)
Manganese
CTs and epidemiology agree

10. New Uncertainty Method: Vitamin D
Dose (µg)
Details
Comments
Uncertainty (UF)
2500;
two trials
Adults and children—4 days duration; second trial in elderly adults treated once every 4 months for 5 years
No adverse effects but duration so short that extrapolation to chronic use is very uncertain; treatment of adults was not daily
>> 1 (how large?)
1250
Healthy men treated for 8 weeks—increased 25 OH D3 but not serum calcium
Possible NOAEL, but with some uncertainty
> 1 (how large?)
1000
Men with multiple sclerosis, treated for 28 weeks, but without a control group
No averse effects, but lack of control group precludes use as NOAEL
>> 1
450
Adults with osteoporosis for 5 years but combined with high-dose fluoride
No adverse effects, but osteoporosis may tolerate more calcium; confounded by fluoride
321
Patients with various diagnoses treated for 6 months; combined with high-dose fluoride
No adverse effects; confounded by fluoride
250
One arm of 1250 µg/day trial listed above; a second trial for 20 weeks
No adverse effects in either trial; duration, replication and statistical power provide confidence; supported by higher dose trials with similar results
Sufficient confidence for UF = 1 and therefore NOAEL of 250 µg/day is the recommended UL
(UL = 250/1)
All lower doses
Multiple trials at 190 µg/day or less; various ages, durations, etc.
Only one trial in 1984 found adverse effects (at 95 µg/day) but that results is contradicted by longer, larger, better trials
No credible and confirmed adverse effects in the dosage range tabulated. LOAEL may be > 1900 µg/day

11. Bioactives Risk Assessments
Ingredient Observed Safe Level
Carnitine 2,000 mg (LCAR equivalents)
Chondroitin (as sulfate) 1,200 mg
Coenzyme Q ,200 mg
Creatine (monohydrate) g
Glucosamine (HCl or sulfate) 2,000 mg
Lutein mg OSL (38 mg animal data)
Lycopene mg OSL (270 mg animal data)
*IADSA 2006; and series of five peer-reviewed articles by Hathcock and Shao in Regulatory Toxicology and Pharmacology, 11

12. Amino Acid Risk Assessments
Nutrient OSL (HOI)
Published
Arginine g
Glutamine g
Taurine g
Others
Not feasible based on human clinical trial data
Animal data extrapolation too uncertain for policy 12

13. Issues for Amino Acid Risk Assessments
No established specific adverse effects for most amino acids
other than total nitrogen load effects on kidney function
Essential amino acids intake from diet only
Non-essential amino acids from diet and biosynthesis
Interactions between a few amino acids, but not most
Reviewed but no UL set by US IOM-FNB
Not reviewed by EFSA or EVM
Much clinical trial data on some amino acids, little on others 13

14. THANK YOU ! John Hathcock, Ph.D. jhathcock@crnusa.org
direct telephone
fax