Zinc oxide (Zinc)

Methionine synthase (MS) and betaine-homocysteine methyltransferase (BHMT) are both zinc (Zn)-dependent methyltransferases and are important in the folate metabolism. The supplementation of zinc has been reported to normalize homocysteine (Pakfetrat et al. 2013; Jing et al. 2015). In addition Zinc and folate have antioxidative properties that counteract reactive oxygen species (ROS) (Ebisch et al. 2007). The supplementation of Zinc has been reported to result in increased folate and vitamin B12 concentration while homocysteine was normalized (Heidarian et al. 2009). 

Zinc as well as Copper play vital roles in retinal function and are essential for antioxidant defence mechanisms in retinal tissue. Zinc and Copper levels in the retinal pigment epithelium (RPE) and choroid complex of patients with AMD were found to be lower than in patients without AMD (Erie et al. 2009). In the eye, zinc is present in high concentration where the majority of ocular zinc is localised to the RPE/ choroid complex (Pao et al. 2018)

In the age-related eye disease study (AREDS), an 11-center double-masked clinical trial with 3640 study participants were supplemented over 6.3 years with zinc (80 mg), as zinc oxide, and copper (2 mg), as cupric oxide, in combination with vitamin C (500 mg) and vitamin E (400 IU) and beta carotene (15 mg) to evaluate the effects on AMD progression and visual acuity (AREDS1 2001). There was no statistically significant serious adverse effect associated with any ingredient of the formulations. A reduction of 25% of the risk for progression of advanced AMD was reported. Even if not mentioned in the study report, we expect, that the included patients of the study actually suffered - as a base disease – of an impairment of the vitamin B metabolism. 

In a multicentre, double-masked randomized follow-up trial, the AREDS formulation was adjusted regarding Zinc dose and beta-carotene (Chew et al. 2014). In particular, the dosage of zinc was reduced from 80 mg to 25 mg based on the rational of reaching the maximum absorption level for zinc (4203 study participants over 5 years). There was no apparent effect of beta carotene elimination or lower–dose zinc on progression to advanced AMD and visual acuity reported (AREDS2 2013). The reported dosage of zinc was metabolically most effective in combination with the antioxidants. In a bioavailability study with formulations containing 25 mg and 80 mg zinc as zinc oxide the absorbed quantity of zinc was determined to be between 7% for tablets and 8-11 % for softgel capsules (Johnson et al. 2014). 

According to EFSA the no observed adverse effect level (NOAEL) for zinc is considered to be around 50 mg/day. This NOAEL is set on the basis of the results of three studies including 19, 21, and 25 healthy subjects respectively, during maximum 90 days. Based on an uncertainty factor (UF) of 2 an upper level (UL) of 25 mg/day is recommended by the EFSA (European Food Safety Authority 2006). Furthermore, in the EFSA 2006 document, toxic effects of zinc supplementation were reported for dietary supplements in excess of 150 mg/day for long periods (European Food Safety Authority 2006). The main toxicity risk is associated with symptoms of copper deficiency which is reflected by adding a copper ingredient to the Ocufolin formulation.

Thus, the dose of 25 mg/day together with approx. 8 – 15 mg/day from dietary zinc intake is - with max. 40 mg/day - significantly above the UL recommended by the EFSA. However, the dose of 25 mg zinc is considered to be safe because of the following considerations: 

a) In the AREDS1 study 80 mg zinc was applied together with copper (2 mg) over 6 years (AREDS1 2001). In this study with 3640 enrolled study participants no statistically significant effect of zinc supplements on hematocrit or serum levels of lipids or copper was observed. Furthermore, it has been reported that supplementation of 80 mg/d of zinc over 2 years did not alter the copper level (Erie et al. 2009; Tittl et al. 1996).Thus, based on these studies a NOAEL of zinc of 80 mg could be suggested. 

b) In the Ocufolin® formulation with 25 mg zinc the ratio of zinc to copper of 40 to 1 is maintained to keep the copper balance. 

c) The total level of 40 mg/day based on 25 mg from Ocufolin® and 15 mg from dietary intake is below the NOAEL of 50 mg set by the EFSA (European Food Safety Authority 2006).

d) In addition, there is no clear scientific rationale for establishing the UF (Renwick 2006), and accepted UL may vary by different Authorities. This is e.g. true for magnesium for which the UL of  250 mg was set by the EFSA (European Food Safety Authority 2006), and the accepted “highest amount” by the Swiss Authorities is 375 mg (VNem 2017).

e) All patients taking the Ocufolin® formulation will be under medical supervision.

Conclusion: The Zinc dosage of 25 mg has been used in the Ocufolin® formulation and combined with 0.67 mg copper in accordance with the AREDs1 ratio. This combination is effective and is considered safe even though the level is higher than the upper maximum defined for zinc.