Unexpected Lessons in Dermatotoxicology: De minimis Magnesium++

Traditional dermatotoxicologic investigations focus on dermatitis as well as potential systemic effects1 but rarely have they focused on trace ions. The following lesson opens new avenues of thought and investigation for intimate care product developers, since the trace ions described may dramatically impact the end product.

Toxic Shock Syndrome
Toxic shock syndrome (TSS), a rare but potentially fatal illness, is caused by toxins produced by bacteria and is characterized by the sudden onset of fever, chills, vomiting, diarrhea, muscle aches and rash. It can rapidly progress to severe and intractable hypotension and multisystem dysfunction. Desquamation, particularly on the palms and soles, can occur 1–2 weeks after the onset of the illness.2 TSS was first reported in children of both sexes in 1978 and subsequently brought to the public’s attention when it became associated with menstruating women using tampons.2

In 1980, an outbreak of TSS occurred involving mostly young women who had been using one brand of superabsorbent tampons. How the tampons caused TSS is partially understood; it has been hypothesized2 that when a superabsorbent tampon is left in place for a prolonged period of time, the tampon becomes a bacteria breeding ground. Others have suggested that the tampon’s superabsorbent fibers can abrade the vagina surface, making it possible for bacteria or their toxins to enter the bloodstream. However, the tampon brand associated with the original TSS epidemic in the 1980s was voluntarily taken off the market by the manufacturer and afterwards, the number of TSS cases declined dramatically.2

Most TSS cases are caused by the Staphylococcus aureus bacteria but can also result from toxins produced by streptococcus bacteria.3 While TSS often occurs in menstruating women, it can also affect men, children and postmenopausal women. In fact, one third of all cases of TSS occur in men. Other risk factors for TSS include skin wounds and surgery.

Magnesium Ions
In 1985, Mills et al.3 reported that the in vitro production of toxic shock syndrome toxin-1 (TSST-1) by Staphylococcus aureus is influenced by the concentration of magnesium ions (Mg++) in the culture medium. The complete removal of Mg++ from the culture medium was found to severely restrict the multiplication of the test staphylococci. On the other hand, with the addition of a small amount of Mg++, toxin production increased; yet with excess amounts of Mg++, toxin production was diminished.2-4 Figure 1 shows the effect of the concentration of magnesium ion on the concentration of TSST-1. The tampon fibers caused the epidemic TSS bound Mg++ and therefore strikingly increased toxin production.5

The vagina is generally anaerobic. However, the production of TSST-1 is oxygen dependent; thus, no toxin is produced anaerobically. Tampons entrap sufficient air in the fiber mesh to introduce measurable amounts of oxygen into the vagina. Kass et al.5 demonstrated that at oxygen concentrations between 5% and 20%, excess amounts of toxin are produced if Mg++ is limiting, and at higher concentrations of Mg++, toxin production is uniformly decreased. In addition, higher incubation temperatures also increase toxin production; however, this effect is greatest at limiting concentrations of Mg++ and is diminished when Mg++ is present in excess.5

Fiber Absorption and Mg++
Binding Polyacrylate fibers are highly absorptive but when treated with Mg++ salts, the resulting fibers do not stimulate increased production of TSST-1, although their absorptive capacity is unchanged. In this manner, the Mg++ combining capacity of a tampon can be separated from its absorptive capacity and thus, highly absorptive fibers can be treated to block the Mg++ binding property. Typically, the peak time of onset of menstruation-related TSS is the fourth day. During early menstruation days, when flow is the heaviest, sufficient Mg++ is present in the effluent to saturate the Mg++ binding capacity of the fibers while leaving sufficient excess to keep toxin production at a minimum. Conversely, when menstrual flow is diminished, as occurs later in menstruation, the amount of Mg++ entering the vagina is low and the fibers bind most of the Mg++, leaving a low Mg++ environment in which toxin production is promoted.5

In summary, Mg++ has a powerful influence on bacterial multiplication and the production of TSST-1. TSS may associate with certain tampon brands but simple highly absorbent fibers are incapable of enhancing the production of TSST-1. When Mg++ concentrations are limited, toxin production is increased, whereas with higher concentration of the Mg++, the production of TSST-1 is suppressed.

Taken together, these insightful epidemiologic and mechanistic investigations of trace ions have explained an important and devastating problem that will assist developers of intimate care products. The lessons learned will also likely bear fruit for other issues of concern. The question now becomes: What will be next?

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1. H Zhai, K-P Wilhelm and HI Maibach, eds. Dermatotoxicology, 7th ed. Florida: CRC Press (2008)
2. EH Kass and J Parsonnet, On the pathogenesis of toxic shock syndrome, Rev Infect Dis, 9 Suppl 5 S482-S489 (1987)
3. JT Mills, J Parsonnet, YC Tsai, M Kendrick, RK Hickman and EH Ka´ss, Control of production of toxic-shock-syndrome toxin-1 (TSST-1) by magnesium ion, J Infect Dis 151 1158-1161(1985)
4. EH Kass, PM Schlievert, J Parsonnet and JT Mills, Effect of magnesium on production of toxic-shock-syndrome toxin-1: A collaborative study, J Infect Dis 158 44-51(1988)
5. EH Kass, J Parsonnet and JT Mills, Role of magnesium ion in the pathogenesis of toxic shock syndrome, Trans Assoc Am Physicians 100 158-163 (1987)

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