Research and analysis

Scientific opinion for the substantiation of a health claim on a combination of lutein, zeaxanthin and meso-zeaxanthin and improved visual performance

Published 1 September 2021

Scientific Opinion for the substantiation of a health claim on a combination of lutein, zeaxanthin and meso-zeaxanthin and improved visual performance pursuant to Article 13(5) of retained Regulation (EC) No 1924/2006^{[footnote 1]}, as amended by the Nutrition (Amendment etc.) (EU Exit) Regulations 2019 and the Nutrition (Amendment etc.) (EU Exit) Regulations 2020

Publication date: 1 September 2021

Application ID: 001UKNHCC

Requestor: Alliance Pharmaceuticals Ltd

Correspondence: [email protected]

This scientific opinion was published by Public Health England (PHE). The UKNHCC is supported by a secretariat that moved into the Office for Health Improvement and Disparities on 1 October 2021.

UKNHCC members

The UK Nutrition and Health Claims Committee (UKNHCC) members are:

• Robert Boyle
• Judith Buttriss
• Francesca Crowe
• Susan Fairweather-Tait (Chair)
• Alison Gallagher
• Darren Greenwood
• Marina Heinonen
• Harry McArdle
• Anders Sjödin

Declarations of interest

Read the UKNHCC register of interests containing all declarations of interests made by members.

UKNHCC secretariat

The UKNHCC secretariat are:

• Haley Bell
• Adrienne Cullum
• Jennifer Garry
• Celia Sabry-Grant

Official observers

The UKNHCC code of practice states that official observers attend UKNHCC meetings to provide updates from their respective nations on science and policy matters of relevance while respecting UKNHCC independence.

The official observers are:

• Alison Black (Welsh Government)
• Chika Edeh (Food Standards Scotland)
• Kerry Gribbin (Food Standards Agency Northern Ireland)
• Debby Webb (Department of Health and Social Care)

Suggested citation

UKNHCC (United Kingdom Nutrition and Health Claims Committee) 2021. Scientific Opinion for the substantiation of a health claim on the combination of lutein, zeaxanthin and meso-zeaxanthin and improved visual performance pursuant to Article 13(5) of retained Regulation (EC) No 1924/2006, as amended by the Nutrition (Amendment etc.) (EU Exit) Regulations 2019 and the Nutrition (Amendment etc.) (EU Exit) Regulations 2020.

UKNHCC disclaimer

The present opinion does not constitute, and cannot be construed as, an authorisation for the marketing of a combination of lutein and zeaxanthin and meso-zeaxanthin, a positive assessment of its safety, nor a decision on whether a combination of lutein and zeaxanthin and meso-zeaxanthin is, or is not, classified as a foodstuff. It should be noted that such an assessment is not foreseen in the framework of retained Regulation (EC) No 1924/2006^{[footnote 1]}, as amended by the Nutrition (Amendment etc.) (EU Exit) Regulations 2019 and the Nutrition (Amendment etc.) (EU Exit) Regulations 2020.

It should also be highlighted that the scope, the proposed wording of the claim and the conditions of use as proposed by the applicant may be subject to changes, pending the outcome of the authorisation procedure foreseen in Article 18(4) of retained Regulation (EC) No 1924/2006^{[footnote 1]} as amended by the Nutrition (Amendment etc.) (EU Exit) Regulations 2019 and the Nutrition (Amendment etc.) (EU Exit) Regulations 2020.

Claim type

Article 13(5): function claim based on a (non-essential) beneficial physiological effect.

Process undertaken by the UKNHCC

The application was received by the UKNHCC on 6 April 2021.

The scientific evaluation procedure started on 9 April 2021.

During its meeting on 18 May 2021, the UKNHCC evaluated the evidence submitted by the applicant.

During its meeting on 16 July 2021, the UKNHCC discussed the scientific opinion.

Following the meeting, the final scientific opinion was agreed via email correspondence.

Summary

Following an application from Alliance Pharmaceuticals Ltd submitted for authorisation of a health claim pursuant to Article 13(5) of retained Regulation (EC) No 1924/2006^{[footnote 1]} as amended by the Nutrition (Amendment etc.) (EU Exit) Regulations 2019 and the Nutrition (Amendment etc.) (EU Exit) Regulations 2020 via the Competent Authority of Great Britain, the United Kingdom Nutrition and Health Claims Committee (UKNHCC) was asked to deliver an opinion on the scientific substantiation of a health claim that “lutein, zeaxanthin and meso-zeaxanthin together improve the visual performance measure known as contrast sensitivity”.

The scope of the application was proposed to fall under a health claim based on newly developed scientific evidence.

The food that is the subject of the health claim is the combination of:

• 10mg lutein
• 2mg zeaxanthin
• 10mg meso-zeaxanthin

The Committee considers that the food, a combination of lutein, zeaxanthin and meso-zeaxanthin, is sufficiently characterised in relation to the proposed claimed effect.

The claimed effect proposed by the applicant is “lutein, zeaxanthin and meso-zeaxanthin together improve the visual performance measure known as contrast sensitivity”. The target population is healthy adults.

The Committee considers that improved visual performance is a beneficial physiological effect.

The applicant identified a total of 7 publications that the applicant suggested met their inclusion criteria to be considered as being pertinent to the claim. This includes 5 randomised controlled trials (RCTs):

• Loughman and others, 2012
• Nolan and others, 2015
• Nolan and others, 2016
• Stringham and others, 2017a
• Stringham and others, 2017b

and 2 reports:

• Loughman, 2013
• Roark and Stringham, 2019

The Committee considers 4 out of 7 publications (Loughman and others, 2012; Roark and Stringham, 2019; Stringham and others, 2017a; Stringham and others, 2017b) as not pertinent to the claim. One report (Loughman and others, 2012) was only available as a conference abstract and another report (Roark and Stringham, 2019) did not assess the effect of the food that is the subject of the claim on visual performance. Two of the RCTs (Stringham and others, 2017a; Stringham and others, 2017b) administered a ratio of lutein, zeaxanthin and meso-zeaxanthin, which differed from the food that is the subject of the health claim. The Committee considers that no conclusions can be drawn from these publications for the substantiation of the claim.

The Committee considers 3 out of 7 publications (Loughman and others, 2012; Nolan and others, 2015; Nolan and others, 2016) to be pertinent to the claim. Two RCTs (Loughman and others, 2012; Nolan and others, 2015) assessed differences in contrast sensitivity from baseline to 6 months within each group but not between the intervention and placebo groups. Therefore, the Committee considers that no conclusions can be drawn from these 2 RCTs for the substantiation of the claim.

One RCT by Nolan and others (2016) reported an improvement in baseline contrast sensitivity at 6 cycles per degree (cpd) by 0.08 in the group administered 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin (the same ratio proposed by the applicant, in the food that is the subject of the health claim) compared with the placebo group at 12 months. The Committee considers this study to have a risk of bias related to potential selective reporting, in particular due to the main results presented not being analysed according to the pre-specified plan published in the protocols (Akuffo and others, 2014; ISRCTN, 2018).

Therefore, in weighing the evidence, the Committee took account of 1 RCT (Nolan and others, 2016) from which conclusions could be drawn.

The Committee concludes there is insufficient evidence to establish a cause and effect relationship between the consumption of 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin together, and improved visual performance measured by contrast sensitivity.

Information provided by the applicant

Applicant name and address

Alliance Pharmaceuticals Ltd
Avonbridge House
Bath Road
Chippenham
Wiltshire
SN15 2BB
England

Food or constituent as stated by the applicant

The food that is the subject of the health claim is a combination of 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin (LMZ).

Health relationship as claimed by the applicant

According to the applicant:

Lutein, zeaxanthin and meso-zeaxanthin together improves the visual performance measure known as contrast sensitivity (CS).

Contrast sensitivity refers to the ability of the visual system to discern differences in the luminance of adjacent areas in a face, object or scene, and detect the edges or borders of the target.

Wording of the health claim as proposed by the applicant

The applicant has proposed the following wording for the health claim: “The combination of lutein, meso-zeaxanthin and zeaxanthin helps maintain normal visual performance by maintaining clarity and contrast of sight.”

Specific conditions of use as proposed by the applicant

The applicant has proposed a daily intake of 10mg lutein, 10mg meso-zeaxanthin and 2mg zeaxanthin (22mg total carotenoids) for a minimum of 12 months to show a beneficial effect in contrast sensitivity. The proposed target population is healthy adults.

Documentation provided

Health claim application on lutein, zeaxanthin and meso-zeaxanthin together improve the visual performance measure known as contrast sensitivity pursuant to Article 13(5) of retained Regulation (EC) No 1924/2006^{[footnote 1]}, as amended by the Nutrition (Amendment etc.) (EU Exit) Regulations 2019 and the Nutrition (Amendment etc.) (EU Exit) Regulations 2020. Application ID: 001UKNHCC. Submitted by Alliance Pharmaceuticals Ltd.

Assessment

1.Characterisation of the food or constituent

1.1 The food that is the subject of the health claim is a combination of 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin derived from the marigold plant (Tagetes erecta). The food also contains sunflower seed oil (75% to 85%) and other ingredients including alpha-tocopherol (0.1% to 1%).

1.2 Lutein, zeaxanthin, and meso-zeaxanthin are xanthophyll carotenoids naturally present in foods. These xanthophylls can be measured in foods by established methods. The Chemical Abstracts Service numbers are:

• lutein (127-40-2)
• zeaxanthin (144-68-3)
• meso-zeaxanthin (31272-50-1)

1.3 The applicant provided an overview of the manufacturing process with reference to accreditations:

• good manufacturing practice (GMP)
• Financial Services Skills Commission (FSSC) 22000
• Hazard Analysis and Critical Control Point (HACCP)
• ISO 9001:2015

A certificate of analysis was provided. No batch-to-batch analysis or information of analytical methods for carotenoids were provided.

1.4 The Committee considers that the food, a combination of 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin, which is the subject of the health claim, is sufficiently characterised in relation to the claimed effect.

2 Relevance of the claimed effect to human health

2.1 The claimed effect proposed by the applicant is “Lutein, zeaxanthin and meso-zeaxanthin together improve the visual performance measure known as contrast sensitivity (CS)”. The target population proposed by the applicant is healthy adults.

2.2 The applicant proposed that the fixed combination of 10mg lutein, 10mg meso-zeaxanthin and 2mg zeaxanthin should be consumed once daily for a minimum of 12 months in order to achieve the claimed effect.

2.3 Vision is a defined function of the eye and nervous system. An increase in vision, reduced loss of vision or maintenance of vision is a beneficial physiological effect for the general population. Visual performance can be measured by using standard tests of visual acuity and contrast sensitivity (EFSA, 2012).

2.4 Changes in contrast sensitivity have been proposed by the applicant as the outcome measure of improved visual performance.

2.5 Contrast sensitivity refers to the ability of the visual system to discern differences in the luminance of adjacent areas in a face, object or scene, and detect the edges or borders of the target.

2.6 The Committee considers contrast sensitivity to be a suitable outcome measure for the scientific substantiation of claims related to increased vision, reduced loss of vision and maintenance of vision.

2.7 The Committee considers that an improvement in visual performance is a beneficial physiological effect.

3. Scientific substantiation of the claimed effect

3.1 The Committee notes that a claim on lutein in combination with zeaxanthin and improved vision under bright light conditions has been assessed by the European Food Safety Authority (EFSA) Panel on Dietetic Products, Nutrition and Allergies (NDA) with an unfavourable outcome (EFSA, 2014). A further claim on meso-zeaxanthin and maintenance of normal vision has been assessed by the EFSA NDA Panel, also with an unfavourable outcome (EFSA, 2010).

3.2 The applicant performed literature searches in Proquest (searching in Embase and Medline) and PubMed using the search terms: (lutein AND zeaxanthin AND meso) AND “contrast sensitivity”. The original search was carried out on 21 September 2020 and was repeated on 11 March 2021. Inclusion and exclusion criteria applied to select the pertinent publications were reported. The applicant included publications on healthy human subjects and all study designs. The applicant excluded single ingredient studies, studies with contrast sensitivity as a secondary endpoint and studies that did not include contrast sensitivity as an endpoint.

3.3 The applicant identified a total of 7 publications, including 5 randomised controlled trials (RCTs) (Loughman and others, 2012; Nolan and others, 2015; Nolan and others, 2016; Stringham and others, 2017a; Stringham and others, 2017b) and 2 reports (Loughman, 2013; Roark and Stringham, 2019).

3.4 The Committee considers 4 out of 7 publications (Loughman and others, 2012; Roark and Stringham, 2019; Stringham and others, 2017a; Stringham and others, 2017b) as not pertinent to the claim.

3.5 The applicant noted that there was no full text available for Loughman (2013) and the Committee considers that, as this report was only available as a conference abstract, it could not be evaluated. A report by Roark and Stringham (2019) provided a description of visual acuity, the measurement of contrast sensitivity and the role of macular carotenoids in visual performance including a summary of the Nolan and others (2016) trial. However, the Committee considers that no conclusions can be drawn from this report, as it did not evaluate evidence for the effects of the food that is the subject of the claim on visual performance.

3.6 Two double-blind, randomised, placebo-controlled trials (Stringham and others, 2017a; Stringham and others, 2017b) investigated the effects of lutein, zeaxanthin and meso-zeaxanthin together on contrast sensitivity at a different ratio compared with the applicant’s food that is the subject of the health claim. Stringham and others (2017a) used 2 carotenoid ratios of 10.86mg lutein, 1.33mg zeaxanthin and 0.94mg meso-zeaxanthin in a 12mg supplement and 22.33mg lutein, 2.70mg zeaxanthin and 2mg meso-zeaxanthin in a 24mg supplement. Stringham and others (2017b) used a carotenoid ratio of 83% lutein, 10% zeaxanthin and 7% meso-zeaxanthin in a 24mg supplement. Therefore, the Committee considers that no conclusions can be drawn from these 2 RCTs for the substantiation of the claim.

3.7 The Committee considers 3 out of 7 publications (Loughman and others, 2012; Nolan and others, 2015; Nolan and others, 2016) as pertinent to the claim.

3.8 A randomised, single-blind, placebo-controlled trial (Loughman and others, 2012) was carried out in 36 healthy adults and was previously evaluated by the EFSA NDA panel in relation to a claim on lutein and zeaxanthin on improved vision under bright light conditions (EFSA, 2014). Participants were randomised to receive 20mg lutein and 2mg zeaxanthin (12 participants); 10mg lutein, 2mg zeaxanthin, and 10mg meso-zeaxanthin (12 participants); or placebo (12 participants) for 6 months. Contrast sensitivity was measured using the Optec6500 Vision Tester with sine wave gratings presented as Gabor patches at spatial frequencies of 1.5, 3, 6, 12, and 18 cycles per degree (cpd). The results for each group by time repeated measures ANOVA were provided. There was no test for a difference in contrast sensitivity at 6 cpd between the intervention group supplemented with 10mg lutein, 2mg zeaxanthin, and 10mg meso-zeaxanthin compared with the placebo group, only within group differences in contrast sensitivity from baseline to 6 months were assessed. The Committee considers that the study duration of 6 months is relevant to the scientific assessment, noting that the applicants’ conditions of use for the claim is 12 months. The Committee considers that no conclusions can be drawn as differences in contrast sensitivity between the intervention and placebo groups from baseline to 6 months were not assessed.

3.9 A randomised, double-blind, placebo-controlled trial (Nolan and others, 2015) was carried out in 62 adults and including 31 patients with Alzheimer’s disease. The Committee considers that the Alzheimer’s disease study arm was not the relevant target population for the claimed effect. The healthy participants (31 participants) were randomised to receive 10mg meso-zeaxanthin, 10mg lutein and 2mg zeaxanthin (15 participants) or placebo (sunflower oil) (16 participants) for 6 months. Contrast sensitivity was measured using the Thomson Test Chart Pro 2000 using Sloan letterset as the test stimuli at 1.2, 2.4, 6, 9.6 and 15.15 cpd. There was no test for a difference in contrast sensitivity between the intervention group compared with the placebo group, only within group differences in contrast sensitivity from baseline to 6 months were assessed. The Committee considers that the study duration of 6 months is relevant to the scientific assessment, noting that the applicants’ conditions of use for the claim is 12 months. The Committee considers that no conclusions can be drawn as differences in contrast sensitivity between the intervention and placebo groups from baseline to 6 months were not assessed.

3.10 In a double-blind, randomised, placebo-controlled trial, Central Retinal Enrichment Supplementation Trials (CREST) by Nolan and others (2016), 53 participants received 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin (the same ratio proposed by the applicant in the food that is the subject of the health claim) in sunflower oil and 52 participants were given a placebo (sunflower oil) for 12 months. The primary outcome was contrast sensitivity at 6 cpd, measured using the Thomson Test Chart Pro 2000^{[footnote 2]} and the Sloan letterset as the test stimuli. There were 42 participants in the intervention group and 36 in the placebo group included in the final analysis after drop-outs and further exclusion due to macular pigment optical density measurements being greater than 0.55 optical density. Results from the repeated measures analysis showed a significant time by group interaction, with contrast sensitivity at 6 cpd being higher by 0.08 in the intervention group compared with the placebo group at 12 months (p equals 0.002). Contrast sensitivity was also higher for 1.2 cpd compared with placebo but not at 2.4, 9.6 or 15.5 cpd. The Committee considers this study to have a risk of bias related to potential selective reporting, in particular due to the main results presented not being analysed according to the pre-specified plan published in the protocols (Akuffo and others, 2014; ISRCTN, 2018).

4. Weighing the evidence

4.1 In weighing the evidence, the Committee took account of 1 RCT (Nolan and others, 2016) from which conclusions could be drawn.

4.2 The Committee concludes there is insufficient evidence to establish a cause and effect relationship between the consumption of 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin together and improved visual performance measured by contrast sensitivity.

Conclusions

On the basis of the data presented by the applicant, the Committee concludes that:

• the food, a combination of 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin, which is the subject of the health claim, is sufficiently characterised in relation to the claimed effect
• the claimed effect relates to improved visual performance. The target population is healthy adults. Improved visual performance is a beneficial physiological effect
• a cause and effect relationship has not been established between the consumption of a combination of 10mg lutein, 2mg zeaxanthin and 10mg meso-zeaxanthin and improved visual performance due to insufficient evidence

References

Akuffo KO, Beatty S, Stack J, Dennison J, O’Regan S, Meagher KA and others (2014). ‘Central Retinal Enrichment Supplementation Trials (CREST): design and methodology of the CREST randomized controlled trials’ Ophthalmic Epidemiology. 21(2):111-123.

EFSA (2010). ‘Scientific opinion on the substantiation of health claims related to meso-zeaxanthin and maintenance of vision (ID 2096) pursuant to Article 13(1) of Regulation (EC) No 1924/2006’ EFSA Journal. 8(2).

EFSA (2012). ‘Guidance on the scientific requirements for health claims related to functions of the nervous system, including psychological functions’ EFSA Journal. 10(7).

EFSA (2014). ‘Scientific opinion on the substantiation of a health claim related to a combination of lutein and zeaxanthin and improved vision under bright light conditions pursuant to Article 13(5) of Regulation (EC) No 1924/2006’ EFSA Journal. 12(7).

ISRCTN (2018). ‘Central Retinal Enrichment Supplementation Trials - enrichment of macular pigment with respect to vision in normal subjects’ (cited on 20 July 2021).

Loughman, J (2013). ‘The role of carotenoids in the eye for visual Performance’ Macular Carotenoids Conference, Cambridge, United Kingdom: Wichtig Editore. p. 606.

Loughman J, Nolan JM, Howard AN, Connolly E, Meagher K and Beatty S (2012). ‘The impact of macular pigment augmentation on visual performance using different carotenoid formulations’ Investigative Ophthalmology and Visual Science. 53:7871-7880.

Nolan JM, Loskutova E, Howard A, Mulcahy R, Moran R, Stack J and others (2015). ‘The impact of supplemental macular carotenoids in Alzheimer’s disease: a randomized clinical trial’ Journal of Alzheimer’s Disease 44:1157-1169.

Nolan JM, Power R, Stringham J, Dennison J, Stack J, Kelly D and others (2016). ‘Enrichment of macular pigment enhances contrast sensitivity in subjects free of retinal disease: Central Retinal Enrichment Supplementation Trials - Report 1’ Investigative Ophthalmology and Visual Science. 57(7):3429-3439.

Roark MW and Stringham JM (2019). ‘Visual Performance in the “real world”: contrast sensitivity, visual acuity and effects of macular carotenoids’ Molecular Nutrition and Food Research. 63(15).

Stringham JM, O’Brien KJ and Stringham NT (2017a). ‘Contrast sensitivity and lateral inhibition are enhanced with macular carotenoid supplementation’ Visual Psychophysics and Physiological Optics. 58:2291-2295.

Stringham JM, Stringham NT and O’Brien KJ (2017b). ‘Macular carotenoid supplementation improves visual performance, sleep quality, and adverse physical symptoms in those with high screen time exposure’ Foods. 6(7).

1. Regulation (EC) No 1924/2006 of the European Parliament and of the Council of 20 December 2006 on nutrition and health claims made on foods. ↩ ↩² ↩³ ↩⁴ ↩⁵

2. Test Chart 2000 Xpert, Thomson Software Solutions, Hatfield, UK. ↩