Investigating the Essentiality and Requirements of Iron from the Ancient to the Present

Abstract

This review discusses the development of studies that evaluated the essentiality and requirements of iron from the ancient to the present. The therapeutic effects of iron compounds were recognized by the ancient Greeks and Romans. The earliest recognition of the essentiality of iron was stated by Paracelsus, a distinguished physician alchemist, in the sixteenth century. Iron was included in the earliest nutritional standard prepared for the Royal Army by E. A. Parkes, the first professor of hygiene. The League of Nations Health Organisation determined average iron requirements based on literature review. In the first US Recommended Dietary Allowances (RDA), the RDA of iron was determined from the results of iron balance studies. In the current Dietary Reference Intakes, iron requirements were determined based on the factorial method with the aid of Monte Carlo simulation for combining basal and menstrual iron losses. Population data analysis is a recently developed alternative that does not use the pre-estimated iron absorption rate and requires the prevalence of inadequacy instead. Population data analysis uses the convolution integral for combining basal and menstrual iron losses to ensure the required accuracy. This review also provides new estimates of hair and nail iron losses.

Appendices

Appendix 1

The original writing by Paracelsus was as follows. “Dann wie ihr sehend daß mangel des Eisens Krankheit macht, … ”.

Appendix 2

Hair Iron Loss

The current author’s estimate of hair iron loss is as follows. The original data are from a composite of males and females. According to Loussouarn et al. [63], the representative value of hair density is 200 hairs/cm² with a 350 μm/day hair growth rate and 80 μm average hair diameter. The standard surface area of the human scalp according to the European Union is 700 cm² [64]. Scalp hair is reasonably assumed as a growing column. Total hair growth rate in volume is 0.246 cm³/day (=hair growth rate in length μm/day × (diameter of hair μm ÷ 2)² × circumference ratio × hair density/cm² × scalp area cm² = 350 × (80 ÷ 2)² × 3.14 × 200 × 700 × 10⁻¹² cm³/day). The specific gravity of hair is 1.31 g/cm³ according to the International Commission of Radiological Protection (ICRP) [65]. Total hair growth rate in weight is 0.322 g/day (=hair growth rate in volume cm³/day × hair specific gravity g/cm³ = 0.246 × 1.31 g/day). The representative value of hair iron content is 25 μg/g (range 5–45 μg/g) according to Iyengar et al. [66]. Therefore, total hair iron loss is estimated to be 8.1 μg/day (= 25 × 0.322).

Nail Iron Loss

Nail iron loss is estimated by the current author as follows. The original data are from a composite of males and females. The average thickness is 0.38 mm and 0.69 mm for fingernails and toenails, respectively, calculated from the reported values by Baden [67]. Baden also reported 1.33 g/cm³ as the density of nail. The total width is 96 mm and 36.8 mm for fingernails [68] and thumb toenails [69], respectively. The nail growth rate in length is 3.47 mm/month and 1.62 mm/month for fingernails and toenails, respectively [70]. Assuming the shape of a nail as a rectangular plate with a growing length, the growth rate of a fingernail in volume is 0.00422 cm³/day (=total width × thickness × growth rate in length ÷ days in a month = 96 mm × 0.38 mm × 3.47 mm/month ÷ 30 day/month = 96 × 0.38 × 3.47 ÷ 30) × 10⁻³ cm³/day) and that in weight is 0.00561 g/day (=growth rate of finger nail in volume × density of nail = 0.0042 cm³/day × 1.33 g/cm³). The growth rate of the thumb toenail in volume is 0.00137 cm³/day (=total width × thickness × growth rate in length ÷ days in a month = 36.8 mm × 0.69 mm × 1.62 mm/month ÷ 30 day/month = 36.8 × 0.69 × 1.62 ÷ 30) × 10⁻³ cm³/day) and that in weight is 0.00182 g/day (=growth rate of thumb toenail in volume × density of nail = 0.00137 cm³/day × 1.33 g/cm³).

The reported mean values of the iron content in fingernails are 12 in males and 13 μg/g in females [71], 64.6 μg/g in males and females [72], and 42 μg/g in males and females [73]. The overall average is 39.7 μg/g. Therefore, the iron loss from finger nails is estimated to be 0.223 μg/day (=iron content in the finger nail × growth rate of finger nail in weight = 39.7 μg/g × 0.00561 g/day). The reported mean value of the toenail iron content in females was 41.4 μg/g [73], while it is not available in males. Therefore, the iron loss from thumb toenails is estimated to be 0.0753 μg/day (=iron content in the thumb toenail × growth rate of thumb toenail in weight = 41.4 μg/g × 0.00182 g/day). Assuming that the iron loss from toenails other than thumb toenails is half of the iron loss from thumb toe nails, the iron loss from nails is estimated to be 0.34 μg/day (=iron loss from finger nails + 1.5 × iron loss from thumb toenails = 0.223 + 1.5 × 0.0753 μg/day).

Epidermal Iron Loss and Sweat Iron Loss

Molin and Wester analyzed epidermal iron content. Based on a median epidermal content of 30.4 μg/g and assumed daily epidermal loss of 0.5–1.0 g, they estimated epidermal iron loss as 15–30 μg/day [74]. In the radio-iron tracer study by Green et al. [32], the mean (±SD) ‘calculated daily iron uptake by skin’ was 0.24 mg/day (± 0.19). The ‘skin’ in their study was a composite of epidermis and dermis after removal of fat and subcutaneous tissue. Thus, their value seems to be the upper limit of iron loss from epidermis plus sebum (see the discussion below) rather than from epidermis alone.

The pure sweat iron loss was estimated by Brune et al. [75]. All subjects were males thoroughly cleansed using a sauna, bath tub, hand brush with soap, shampoo, and pumice-stone. Sweat from the whole body in the sauna was collected twice with an interval. A cell-free sweat sample was obtained by centrifugation and filtration. At the steady state (second collection), the mean iron content (±SD) was 22.50 μg/L (± 2.29) in the cell-free sweat and 119.0 μg/L (± 18.5) in the cell-rich sweat (i.e., untreated), while at the first collection, it was 50.70 μg/L (± 7.24) in the cell-free sweat and 213.0 μg/L (± 39.8) in the cell-rich sweat. By rough estimation, about 80% of surface losses are estimated to be derived from desquamated cells or cell debris.

The most accurate surface iron loss was reported by Jacob et al. [76]. They measured surface iron losses from the whole bodies of males by 88 daily collections over 4 to 9 months under trace element-controlled conditions. The bodies of the subjects were thoroughly cleansed and covered with a union paper suit and socks with plastic boots. Iron left in the subject’s wearing, pillow case, sheets, and body washes was collected for analysis of iron. The mean (±SD) percutaneous or surface iron loss was 0.33 mg/day (± 0.15). We have to be careful about this surface loss as it did not include hair and nail iron losses.

Assuming that 80% of surface iron loss originates from desquamated cells or cell debris, the iron loss derived from desquamated cells or cell debris accounts for about 0.25 mg. This amount is far larger than the epidermal iron loss (0.01–0.03 mg) estimated by Molin et al. [74] and close to the estimate by Green et al. [32]. This gap can be attributed to iron in sebum. Residual skin surface components (RSSC) derived from sebum, sweat, and epidermal lipids were collected with cigarette paper or absorbent paper [77]. The collected RSSC was dried and weighed and shown as sebum weight. The sebum secretion from forehead skin is about 0.1 mg/cm² for 3 h [77]. Sebum is secreted from sebaceous glands by a holocrine process. Sebum is essentially an aggregate of disintegrated lipid-producing cells [78], presumably containing a considerable amount of iron, which has not yet been measured.

The reported values of hair iron content were distributed over a wide range [66], and the surface of the human body is very prone to contamination and exogenous deposition of metal elements [79], especially dyeing and marcelling of the hair [80]. Although they are variable, the contribution of hair, nail, and epidermis in iron loss is small.

Endogenous Iron Loss from the Gastrointestinal Tract

The endogenous iron loss from the gastrointestinal tract was measured by Green et al. using radio-iron tracer [32]. The mean (±SD) of endogenous iron loss was 0.51 mg (± 0.12). Based on the study by Green et al., the representative value of daily iron loss from urine, gastrointestinal tract, and skin was established as approximately 0.08, 0.6, and 0.2 to 0.3 mg/day, respectively, in the DRI [31]. Croft showed evidence that intestinal iron loss is derived from epithelial loss by measuring DNA and iron in the washings of the small intestine after intravenous injection of ⁵⁹Fe in rats [81].