Parabens Parabens, the alkyl esters of p- hydroxybenzoicacids (PHBA) (68), are a group of non- persistent chemicals (74) usedindividually or in mixtures to reach preferred antimicrobial- and preservativeeffects. They are especially effective against molds and yeasts, and are widely(18) used because of their antimicrobial-, and relatively non- irritating- andnon- sensitizing properties. Parabens have low acute toxicity (9, 68, 77), buthave been associated with allergy. They also have low cost, (9) and arepH-stable (i.e.
they help in preventing too rapid product degradation) (68,77). Short chained parabens are more hydrophilic and the long chained are morelipophilic (figure 5). When the chain length of the paraben increases, theresistance to hydrolysis and antimicrobial activity increase (9), but watersolubility decrease.
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As a consequence, methylparaben (MP) and propylparaben(PP), which have shorter chains, are the ones most used in cosmetics (9). MPand PP are however also preferred for use in foods (68, 77). MP, PP,butylparaben (BP), ethylparaben (EP), heptyl- (HP) and benzylparaben (BzP), isopropyl-and isobutylparaben are homologous (30, 68, 77). The use of parabens havecaused concern due to their possession of estrogenic- (9) and antiandrogenicproperties (65, 66) (i.e. they can act as ER agonists and AR antagonists).Parabens may affect health at lower concentrations and more precise than non-receptor mediated mechanisms, because of their capability binding to ERs (69).Several studies, both in vitro and in vivo, have demonstrated parabensdisruptive effects in physiologically important mechanisms.
The disruptiveeffect most described in research, is the parabens ability to bind to humanERs, and 28 thereafter regulate gene expression and cell growth in estrogen-responsive cells through ER mediated mechanisms (figure 6). But parabens doalso have the potential to antagonize AR– mediated effects in androgen-responsive cells, and to behave as sulfotransferase enzyme (SULTs) inhibitors(10) and act on the regulation of steroids (61). In fact, both in vitro and invivo assays show all common native parabens possess estrogenic effects (10).And the longer paraben chain, from MP to n- BP, the larger are these effects(9, 78). A higher estrogenic effect is also associated with branching in thealkyl chain, from n- PP to isopropylparaben (79), and n- BP to isobutylparaben(80).
However, the estrogenic effects have been detected to be 10 000 to 100000- fold weaker than natural 17?- estradiol, after subcutaneous administrationto rats (78). According to Darbre et al. (80), isobutylparaben has the strongestestrogenic effect. PHBA, parabens main metabolite, have a weaker estrogeniceffect than native parabens (10).
Despite unclear estrogenicity of glycine-,sulfate- and glucuronide conjugates, the Scientific Committee on ConsumerSafety (SCCS) (81) has concluded that they are most likely not estrogenic. Thisconclusion was mainly based on the fact that steroid conjugates themselvescause no effect at the receptor (81). In theory, as a consequence of parabensestrogenic- and antiandrogenic effects, parabens may cause diseases related tothe endocrine system.
Reproductive diseases and endocrine cancers have been ofspecial concern. For instance, parabens have been detected in largerconcentrations in the axilla area compared to the lateral, mid and medial sideof the breast, and a link between parabens in underarm cosmetics and breastcancer has been suggested (82). No association, however, has been made betweensingle parabens and breast cancer. A recent study by Charles and Darbre (83) onthe other hand, showed that combinations of parabens in human breast tissuesare large enough to stimulate proliferation of MCF- 7 breast cancer cells. Insome tissue samples, all single parabens measured were detected atconcentrations below “no- observedeffect- concentration” (NOEC) (83).
Thisshows the importance to also consider mixtures of EDCs