Download Safety of Amino Acids as Essential Building Blocks of Human

4th Asia-Pacific International Food Safety Conference & 7th Asian Conference on Food and Nutrition Safety, October 11-13, 2016, Penang, Malaysia
Safety of Amino Acids as Essential Building
Blocks of Human Nutrition
Miro Smriga, PhD
International Council on Amino Acid Sciences (ICAAS)
www.icaas-org.com
Brussels, Belgium
What is ICAAS?
A scientific NGO, an observer with CODEX
Member Companies of
1.
2.
Our purpose:
• To help establish UPPER LIMITs for amino acid intake
from foods or supplements.
• To promote the use of HIGH QUALITY amino acids
3.
4.
5.
6.
7.
We:
• sponsor clinical safety research.
• Organize international Amino Acid Assessment
Workshops (J. Nutr.) and other symposia
• interact with national regulatory bodies, WHO/FAO
structures and the US/EU Pharmacopeia
8.
9.
10.
Ajinomoto Co., Inc.
Evonik Rexim
Omnichem
Kyowa Bio Co., Ltd.
GlaxoSmithKline
Real Nutriceuticals Group Ltd.
Otsuka Pharmaceutical Co. Ltd.
Suntory Ltd.
Meiji Dairies Corporation
Kyowa Hakko Europe
Japan & USA
Germany
Belgium
Japan
United Kingdom
China
Japan
Japan
Japan
Germany
4th Asia-Pacific International Food Safety Conference & 7th Asian Conference on Food and Nutrition Safety, October 11-13, 2016, Penang, Malaysia
What are Amino Acids?
Scientific Advisory
Committee
Amino acids = an amino group and a carboxyl group
(Alkaline)
1.
2.
3.
4.
5.
6.
Prof. D. Bier (Baylor College of Medicine, Nutrition, USA)
Prof. S. Morris (Univ. Pittsburgh, Biochemistry, USA)
Prof. L. Cynober (Paris 5th Univ., Nutrition, France)
Prof. R. Elango (Univ. British Columbia, Canada)
Prof. M. Kadowaki (Niigata Univ., Nutrition, Japan)
Prof. P. Stover (Cornell Univ., USA)
This part is different
in every amino acid
This part is the same
in every amino acid
C
䠟䠫䠫䠤
Peptide
Pept
Pe
ptid
pt
ide
id
e
bond
Why Amino Acids (1)?
Glycine Tyrosine
Aspartic Acid
Serine
Glutamate
Proline
Cysteine
Asparagine
Alanine
Valine
Arginine
Isoleucine
Histidine
Amino-group
䠟䠫䠫䠤
H
䠤2䠪
Carboxyl-group
6
Approximately 100,000 different proteins are made from
20 amino acids!
Threonine
Phenylalanine
Glutamine
䠤䠎䠪
Why Amino Acids (2)?
Tryptophan
Leucine
(Acid)
Methionine
Lysine
Essential Amino Acids
Amino Acids differ from Proteins:
• No allergenicity
• Endogenous substances present in a diet
• Efficient absorption
• Easy utilization
• Taste properties
• Cost-effective & environmentally-friendly production
Building the
body
Protecting the
body
Keratin (nails, hair),
collagen (skin), actin,
myosin (muscle)
Immunoglobulin
(lgG, etc.)
Providing
Components in
blood
Albumin,
hemoglobin...
Controlling
reactions
Enzymes,
neurotransmitters,
hormones…
4th Asia-Pacific International Food Safety Conference & 7th Asian Conference on Food and Nutrition Safety, October 11-13, 2016, Penang, Malaysia
Safety risk of nutrients
Fermentation Products
Glucose syrup
(Fermentation broth)
Byproducts
Purified
Crystalized
Amino acids
Organic acids
Alcohol (spirits)
Beer
for example
Micro-organism
Yeast extracts
for example
Glucose
Metabolites
Animal
data
NOAEL
Increasing intake
NOAEL: No Observed Adverse Effect Level
SF:
Safety Factor
ADI:
Acceptable Daily Intake = UL
Incidence of adverse effects
Incidence of adverse effects
100%
ADI
Incidence of
deficiency
Incidence
of adverse
effects
Intake
Classical Toxicology
SF
Breach of specifications
Low purity
0%
Upper limits (UL) for amino acid use
At least 100
Harmfulness
100%
Problems with Applying Classical
Toxicology to Amino Acids
Alternative Model
NOAEL
(male rat)
100%
UL
Human
data
NOAEL
Increasing intake
UL: Upper Limit
The highest level of daily nutrient
intake that is likely to pose no risk of
adverse effects to almost all
individuals in the general population.
ADI
(male human, 80 kg BW)
Leucine
3.3 g/kg/D
2.6 g/D
Isoleucine
1.6 g/kg/D
1.28 g/D
Valine
3.2 g/kg/D
2.56 g/D
Lysine
3.4 g/kg/D
2.72 g/D
Glutamine
0.8 g/kg/D
0.64 g/D
Arginine
3.3 g/kg/D
2.64 g/D
Below average
dietary intake!
4th Asia-Pacific International Food Safety Conference & 7th Asian Conference on Food and Nutrition Safety, October 11-13, 2016, Penang, Malaysia
Leucine intake from a diet
Mean U.S. Intake :
5.9 g/day
95th Percentile U.S. Intake :
14.1 g/day
1988-1994 NHANES III, for all age/gender groups, food + supplements
(DRIs: National Academies Press, 2001)
Excess leucine intake
take
Leucine target: muscle
10
8
Muscle soreness
induced by squat exercise
(cm scale)
6
Placebo
4
No evidence of harm,
no side effects. Max
oxidative potential of
leucine in a 80 kg
human is 44 g/day
2
Leucine
0
Before
After 1
2
3
4
Days after exercise
Elango et al., AJCN 2012; 96: 759-767
Shimomura et al., J. Nutr. 2006; 136: S529-S562
Event-free survival (%)
BCAA (12 g/day for 3 years) for
patients with Liver Cirrhosis
Launched in 1996 as a
prescription drug
Protocol:
Subjects: Adult females (non-athletes)
Dose:
5g Leucine (15 min < exercise)
Method: subjective analogue scale
Logrank test P=0.015
Estimated hazard ratio 0.674
100
Arginine intake from a diet
Mean U.S. Intake :
4.2 g/day
95th Percentile U.S. Intake :
10.1 g/day
1988-1994 NHANES III, for all age/gender groups, food + supplements
(DRIs: National Academies Press, 2001)
80
60
Excess arginine intake (3 months study)
40
BCAA (N=314)
Diet Therapy (N=308)
20
0
0
No evidence of harm, no side effects found
up to 30.0 g/day
1
2
3
Years after the initiation of therapy
Marchesini et al, Gastroenterology 2003; 124: 1792-1801
Muto et al, Clin Gastroenterol Hepatol. 2005; 3: 705-713
McNeal et al., J. Nutr. 2016 (in press)
Wu et al., Amino Acids. 2016; 48(7): 1541-52
4th Asia-Pacific International Food Safety Conference & 7th Asian Conference on Food and Nutrition Safety, October 11-13, 2016, Penang, Malaysia
Tryptophan intake from a diet
Mean U.S. Intake :
0.9 g/day
95th Percentile U.S. Intake :
2.1 g/day
1988-1994 NHANES III, for all age/gender groups, food + supplements
(DRIs: National Academies Press, 2001)
Current Phase of ICAAS Clinical Trials
• Methionine … finished
• Glutamate … finished
• Glutamine, Lysine … in preparation
Excess tryptophan intake (3 months study)
No evidence of harm, no side effects found
up to 5.0 g/day
Hiratsuka et al, J Nutr. 2013; 143: 859-866
Specifications
Harmfulness
100%
Breach of specifications
Low purity
Incidence of
deficiency
Incidence
of adverse
effects
0%
Intake
ULTIMATE GOAL:
To establish safety framework for high quality amino
acids …. “industry responsibility”
Rogers & Smriga, Eur. J. Risk Regulation 2012; 2: 161-168
How to address specification issues?
Since 2009; ICAAS has been cooperating
with the U.S. Pharmacopoeia Convention
on the Food Chemical Codex specifications
for amino acids
4th Asia-Pacific International Food Safety Conference & 7th Asian Conference on Food and Nutrition Safety, October 11-13, 2016, Penang, Malaysia
ICAAS & USP: “insoluble foreign matter”
The number of insoluble
matter correlated to the
frequency of samples
with bacterial
contamination.
Case of tryptophan
• A deadly disease (Eosinophilia Myalgia Syndrome) was
caused in 1989 by 1 LOT of a tryptophan product from
1 manufacturer with poor quality controls
• Specifications were in compliance with FCC.
PAA
3-(phenylamino)alanine
1+
+
1
&22+
Hartmann E. Am J Psychiat 1997; 134: 366-370
Schneider-Helmert D, Spinweber CL. Psychopharmacology 1986; 89: 1-7
Fernstrom JD. J Nutr 2012; 142: 2236S-44S
Current supplements: HPLC
Current Stage of ICAAS Effort to Improve
Amino Acid Specifications
• Working on USP monographs for BCAA
New FCC req.: Impurities before Trp peak: 100 ppm & Impurities after Trp peak: 300 ppm
207 ppm
• Cooperating with Brazil ANVISA on specifications and
adulteration issues
249 ppm
ULTIMATE GOAL:
To modernize amino acid monographs in both USP and
FCC
113 ppm
522 ppm
174 ppm
340 ppm
4th Asia-Pacific International Food Safety Conference & 7th Asian Conference on Food and Nutrition Safety, October 11-13, 2016, Penang, Malaysia
Safety risk of nutrients with evolutionary
presence in a human diet
Harmfulness
100%
Protein & Amino Acid Requirements
(WHO/FAO Expert Consultation)
Breach of specifications
Low purity
Incidence of
deficiency
Incidence
of adverse
effects
0%
Intake
The most wide-spread amino acid deficiencies
Cereal based diets: Lysine
Maize based diets: Tryptophan, Lysine, Methionine
mg/kg/day
mg/kg/day
Amino Acid
1985
2007
Histidine
Isoleucine
Leucine
Valine
Lysine
Methionine + Cysteine
Threonine
Tryptophan
Phenylalanine + Tyrosine
10
10
14
10
12
13
7
3.5
14
10
20 (2.0 times)
39 (2.8 times)
26 (2.6 times)
30 (2.5 times)
15 (1.2 times)
15 (2.1 times)
4 (1.14 times)
25 (1.8 times)
Results of the Lys fortification trials (3
months) conducted in 2000s
1.
2.
3.
General poor nutrition: Leucine, Isoleucine, Valine
4.
Growth improvement in children (Ghana, Syria,
China, Pakistan)
Improvement of nutritional protein status and
immune status (Pakistan, China, Ghana, Syria)
Decrease in diarrhoea incidence (Bangladesh, Syria,
Ghana)
Improvement in mental health (long-term anxiety,
Syria).
4th Asia-Pacific International Food Safety Conference & 7th Asian Conference on Food and Nutrition Safety, October 11-13, 2016, Penang, Malaysia
Summary
Summary
Ongoing fortification initiative …
Public Private Partnership (West Africa)
Amino acids are a “case study” of food ingredients
normally present in food/human body.
1. Essential and semi-essential amino acids seem to be
safe at very high levels of intake, if specifications are
appropriately controlled.
2. Deficiency of essential amino acids is one of the
unrecognized nutritional problems. It affects
especially growing children in economically underdeveloped regions.
I.
II.
III.
Among staple foods, only cereal supply is marginally growing through imports
Meat/milk supplies are slightly declining
Cassava and yam supply grow only through surface expansion (unsustainable)