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Parabens toxicity to skin and other organs

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LASER AND COSMETIC NEWS
PARABENS TOXICITY TO SKIN AND OTHER ORGANS
Macrene Alexiades-Armenakas MD PhD
Assistant Clinical Professor, Yale University School of Medicine, New Haven, CT; Private Practice, Dermatology and Laser Surgery, New York, NY
Parabens, including methylparaben, butylparaben, isobutyl-
paraben, and their metabolite, p-hydroxybenzoic acid, have
been extensively used in skin care, cosmetics, foods, and
pharmaceutical agents as antimicrobial preservatives for
many years. Published reports have emerged in recent years
implicating parabens as potential carcinogens in breast can-
cer, uterine cancer, and most recently, skin cancer.
The estrogenic effects and potential link to breast cancer
have been the most extensively studied adverse outcomes
from parabens. Most of these published reports are from the
work of Darbre and colleagues in the United Kingdom. In
2002, this group reported that parabens exhibit estrogenic ac-
tivity in vitro and in vivo, with such activity directly corre-
lating with the length of the alkyl chain from methylparaben
to butylparaben to isobutylparaben.1,2 This activity was meas-
ured in human breast cancer cell lines (MCF7) by the dis-
placement of tritiated estradiol from its cytosolic receptor and
by upregulation of expression of an estrogen responsive re-
porter gene.2Increased proliferation in breast cell lines and
in murine uterine tissue in vivo were also reported in re-
sponse to exposure to benzylparaben.1,2 Conversely, isobutyl-
paraben had no effect on growth of estrogen-unresponsive
MDA-MB-231 human breast cancer cells.2When n-butyl-
paraben was compared to 17beta-estradiol in its effects on
MCF7 cell lines, the growth responses of the cells were sim-
ilar; however, the gene expression induced by each agent was
different, suggesting that while proliferative effects via the es-
trogen receptor may be similar, their downstream genetic ef-
fects are distinct.3The aforementioned data are in contrast
to a 2002 article from a group in the United States which re-
ported nontoxic effects of methylparaben administered to rats
at a dose of up to 5700 mg/kg and which stated that methyl-
paraben is not carcinogenic or mutagenic.4Overall, the vast
majority of the studies indicate estrogenic effects in vitro and
in vivo, though additional centers are needed to reproduce or
refute these findings.
A related question was whether the removal of the ester
group from parabens in the formation of its metabolite
p-hydroxybenzoic acid eliminated these estrogenic activities.
The metabolite of paraben esters, p-hydroxybenzoic acid, was
subsequently tested for estrogenic activity and its effects on
breast cancer cell lines. It was found that the abilities to
displace estradiol from its estradiol cytosolic receptor and to
upregulate estrogen responsive reporter genes were demon-
strated for the p-hydroxybenzoic acid metabolite.5On the
other hand, the activity on downstream gene expression and
cell proliferation was lower for the metabolite as compared
to methylparaben, suggesting that removal of the ester group
may diminish but not eliminate the estrogenic effects in
these assays.5In a prior study, a group in Denmark was unable
to detect findings of uterine growth secondary to
p-hydroxybenzoic acid exposure in the mouse model at
1000 mg/kg body weight per day, though a weak estrogenic
response of uterine growth was demonstrated in the rat at
600 mg/kg/body weight per day.6A study evaluating the
estrogenic effects of p-hydroxybenzoic acid on spermato -
genesis in rats demonstrated no decrease in the weights of
testes and other male sex organs or in testosterone levels at
a dose of 1000 mg/kg body weight per day.7This suggests that
the estrogenic effects may not impact male sex organs.
Most recently, parabens have been reported to potentiate ox-
idative stress, nitric oxide production and lipid peroxidation
following ultraviolet (UV) light exposure in cultured skin
keratinocytes.8This is of particular concern since parabens
are commonly used as preservatives in skin care products.
Thus, in addition to systemic uptake and potential for es-
trogenically-induced breast and other end organ cancers,
parabens may directly augment UV-induced cellular damage
in skin, potentially linking it to skin cancer. Clearly, more re-
search must be dedicated in this area of paraben-mediated
potential skin toxicity in light of the fact that numerous skin
care cleansers, creams, and pharmaceuticals contain parabens
as their main preservatives.
In summary, a body of published research is accumulating
regarding the toxicity of parabens and their metabolites in
several organs including breast, uterus and skin. The poten-
tial for carcinogenesis must continue to be rigorously analyzed
so that alternative forms of nontoxic preservatives may serve
as their replacement in foods, pharmaceuticals, cosmetics,
and skin care products.
References
1. Darbre PD, Byford JR, Shaw LE, Horton RA, Pope GS, Sauer MJ.
Oestrogenic activity of isobutylparaben in vitro and in vivo. J Appl
Toxicol. 2002;22:219-226.
Laser and Cosmetic News covers the latest advances in laser surgery, light technology, phototherapy, and cosmetic surgery.
New and emerging therapies, noteworthy publications, and exciting meeting developments will be highlighted. Contro-
versies and opinions about the future in this field will be addressed. The aim of this column is to keep you abreast of the
cutting edge in laser and cosmetic surgery.
© 2008-Journal of Drugs in Dermatology. All Rights Reserved.
This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
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JOURNAL OF DRUGS IN DERMATOLOGY
JANUARY 2008 • VOLUME 7 • ISSUE 1
LASER AND COSMETIC NEWS
2. Darbre PD, Byford JR, Shaw LE, Hall S, Coldham NG, Pope GS,
Sauer MJ. Oestrogenic activity of benzylparaben. J Appl Toxicol.
2003;23:43-51.
3. Pugazhendhi D, Sadler AJ, Darbre PD. Comparison of the global
gene expression profiles produced by methylparaben, n-butyl-
paraben and 17beta-oestradiol in MCF7 human breast cancer cells.
J Appl Toxicol. 2007;27:67-77.
4. Soni MG, Taylor SL, Greenberg NA, Burdock GA. Evaluation of
the health aspects of methyl paraben:a review of the published lit-
erature. Food Chem Toxicol. 2002;40:1335-1373.
5. Pugazhendhi D, Pope GS, Darbre PD. Oestrogenic activity of p-hy-
droxybenzoic acid (common metabolite of paraben esters) and
methylparaben in human breast cancer cell lines. J Appl Toxicol.
2005;25:301-309.
6. Hossaini A, Larsen JJ, Larsen JC. Lack of oestrogenic effects of
food preservatives (parabens) in uterotrophic assays. Food Chem
Toxicol. 2000;38:319-323.
7. Oishi S. Lack of spermatotoxic effects of methyl and ethyl esters of
p-hydroxybenzoic acid in rats. Food Chem Toxicol. 2004;42:
1845-1849.
8. Handa O, Kokura S, Adachi S, Takagi T, Naito Y, Tanigawa T,
Yoshida N, Yoshikawa T. Methylparaben potentiates UV-induced
damage of skin keratinocytes. Toxicology. 2006;227:62-72.
© 2008-Journal of Drugs in Dermatology. All Rights Reserved.
This document contains proprietary information, images and marks of Journal of Drugs in Dermatology (JDD).
No reproduction or use of any portion of the contents of these materials may be made without the express written consent of JDD.
If you feel you have obtained this copy illegally, please contact JDD immediately.
Do Not Copy
Penalties Apply
... If we consider that parabens are very well tested and penetrate the skin to a small extent, there is a growing number of people -experts from the medical community, members of ecological and pro-consumer organizations -who question the safety of these substances [26][27][28]. It is postulated that the most common parabens present in cosmetics are associated with the following issues: ...
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Since the alkyl esters of p-hydroxybenzoic acid (parabens) can be measured intact in the human breast and possess oestrogenic properties, it has been suggested that they could contribute to an aberrant burden of oestrogen signalling in the human breast and so play a role in the rising incidence of breast cancer. However, although parabens have been shown to regulate a few single genes (reporter genes, pS2, progesterone receptor) in a manner similar to that of 17beta-oestradiol, the question remains as to the full extent of the similarity in the overall gene profile induced in response to parabens compared with 17beta-oestradiol. The GE-Amersham CodeLink 20 K human expression microarray system was used to profile the expression of 19881 genes in MCF7 human breast cancer cells following a 7-day exposure to 5 x 10(-4) M methylparaben, 10(-5) M n-butylparaben and 10(-8) M 17beta-oestradiol. At these concentrations, the parabens gave growth responses in MCF7 cells of similar magnitude to 17beta-oestradiol. The study identified genes which are upregulated or downregulated to a similar extent by methylparaben, n-butylparaben and 17beta-oestradiol. However, the majority of genes were not regulated in the same way by all three treatments. Some genes responded differently to parabens from 17beta-oestradiol, and furthermore, differences in expression of some genes could be detected even between the two individual parabens. Therefore, although parabens possess oestrogenic properties, their mimicry in terms of global gene expression patterns is not perfect and differences in gene expression profiles could result in consequences to the cells that are not identical to those following exposure to 17beta-oestradiol.