Risk Assessment of "Other Substances" – L-proline
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Date
2018-12
Journal Title
Journal ISSN
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Publisher
Science Domain International
Abstract
The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has, at the request of the Norwegian Food Safety Authority (Mattilsynet; NFSA), assessed the risk of "other substances" in food supplements and energy drinks sold in Norway. VKM has assessed the risk of doses given by NFSA. These risk assessments will provide NFSA with the scientific basis while regulating "other substances" in food supplements.
"Other substances" are described in the food supplement directive 2002/46/EC as substances other than vitamins or minerals that have a nutritional and/ or physiological effect. It is added mainly to food supplements, but also to energy drinks and other foods. In this series of risk assessments of "other substances" VKM has not evaluated any claimed beneficial effects from these substances, only possible adverse effects.
The present report is a risk assessment of specified doses of L-proline in food supplements, and it is based on previous risk assessments and articles retrieved from literature searches.
According to information from NFSA, L-proline is an ingredient in food supplements sold in Norway. NSFA has requested a risk assessment of 50, 500, 1000, 1500 and 1800 mg/day of L-proline from food supplements.
L-proline is considered a non-essential amino acid as it can be synthesised from arginine via the urea cycle in liver, and from glutamine/glutamic acid in the intestinal epithelium. In addition, L-proline is ingested through the diet. All protein rich foods provide L-proline, and animal proteins from milk and meat are particularly abundant sources. A dietary requirement for proline in healthy humans has not been estimated since proline is not considered an essential amino acid. Data on dietary intake of L-proline in Norway are not available. In the third US National Health and Nutrition Examination Survey (NHANES III; 1988-1994), overall mean intake of L-proline from food and supplements was 5.2 g/day.
A previous report from the Institute of Medicine (2005) cited one small uncontrolled patient study (n=4) and two animal studies, none of which assessed the toxicity of L-proline in a dose-response manner. The report concluded that a tolerable upper intake level for L-proline could not be determined.
In a risk grouping of amino acids from VKM (2011), proline was categorised as having potentially moderate risk, based on the scarce literature and the notion that amino acids are generally bioactive compounds. It was stated that "no conclusion can be drawn on a scientific basis due to lack of adequate scientific literature. Nor will it be possible to conduct a risk assessment until further studies are available".
Three systematic literature searches without restriction on publication year were performed for the current risk assessment, aimed at identifying adverse effects of L-proline supplementation in human and animal studies. In humans, one uncontrolled experimental study was identified where a single oral dose of 500 mg/kg bw L-proline was administered as a growth hormone stimulatory agent to 20 children with hyposomatotropic dwarfism and 20 healthy children. No adverse effects were observed. In animals, one relevant subchronic (90 days) toxicological dose-response study in rats was included and forms the basis for the current risk assessment. In that study, performed in accordance with official guidelines from the Japanese Ministry of Health, Labour and Welfare, there were no indications of toxicity at the highest dose given through a powder diet (5.0% L-proline). This dose corresponded to 2773 mg L-proline/kg bw per day and was used as a no-observed-adverse-effect-level (NOAEL).
Studies to set a tolerance level for L-proline for children or adolescents have not been found. Therefore, an assumption is made that these age groups have similar tolerance as adults relative to their body weight.
To evaluate the safety of the specific doses given by NFSA, margin of exposure (MOE) was calculated with use of 2773 mg L-proline/kg bw per day as NOAEL. For the highest dose (1800 mg/day) MOE is 67 (= 2773* 43.3/1800) in children 10 to <14 years (default body weight 43.3 kg), and 94 (= 2773* 61.3/1800) in adolescents 14 to <18 years (default body weight 61.3 kg). For the dose of 1500 mg/day, the MOE in children is 80. MOE for all the other doses and age categories are above 100.
Based on the magnitude of MOE, the lack of adverse effects at the highest dose tested (current NOAEL) and the notion that L-proline is a nutrient that is synthesised endogenously from other amino acids in addition to a dietary intake in the magnitude of 5 grams per day, VKM concludes that:
In adults (≥18 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day Lproline in food supplements are unlikely to cause adverse health effects.
In adolescents (14 to <18 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-proline in food supplements are unlikely to cause adverse health effects.
In children (10 to <14 years), the specified doses 50, 500, 1000, 1500 and 1800 mg/day L-proline in food supplements are unlikely to cause adverse health effects. Children younger than 10 years were not within the scope of the present risk assessment.
Description
Keywords
L-proline, food supplement, adverse health effect, negative health effect, Norwegian Food Safety Authority, Norwegian Scientific Committee for Food Safety, other substances, risk assessment, VKM
Citation
Holvik Kristin, Frøyland Livar, Haugen Margaretha, Henjum Sigrun, Løvik Martinus, Skålhegg Bjørn Steen, Stea Tonje Holte, Strand Tor A., Tell Grethe S., Iversen Per Ole. Risk Assessment of "Other Substances" – L-proline. European Journal of Nutrition and Food Safety. 2018 Dec; 9(1): 25-27