Fabio Della Marra

In vitro skin permeation and retention of parabens from cosmetic formulations

Dear Sir, The recent paper published in the International Journal of Cosmetic Science titled ‘in vitro skin permeation and retention of parabens from cosmetic formulations’ [1] raises a few issues. It is disappointing to see three references to Darbre et al. [2] on two counts: (i) Two of the three references cited this paper as a primary source of the information quoted, although, in fact, it was a secondary source as the Darbre paper itself referred to earlier publications. The reference to parabens being permitted in cosmetics at concentrations up to 1% originally came from Elder [3], and the figure of 1% is relevant only to Japan and countries that follow the Japanese regulations. In the EU, and many other territories, the maximum concentration permitted is 0.8% (as total parabens, with a maximum of 0.4% for individual esters). Whilst the statement is broadly correct, it should be put in the correct context, particularly in a publication aimed at cosmetic scientists. The second quote referred to the frequency of use of parabens as being 99% in leave-on and 77% in rinse-off products. Darbre et al. took this information from Rastogi et al. [4], and stated that this was based on a survey of 215 cosmetic products. This is a very small sample from the tens of thousands of cosmetic products on the market, and the data are statistically meaningless, and presented out of context by Pedersen et al. as they could be interpreted as being an accurate representation of the market position. Whilst it is likely that parabens are present in a great majority of leave-on products, it is extremely unlikely that they enjoy 99% dominance. (ii) The inclusion of the third reference to Darbre et al. is of particular concern, especially in a journal for cosmetic scientists, as the majority of the cosmetic science community, and many beyond it, dispute the implied connection between the presence of parabens in breast tumour tissue and breast cancer. This implied connection has been seized upon as fact by many ‘anti-chemicals’ groups and used to feed media with scare stories manipulating public opinion against parabens in particular. Furthermore, there is serious doubt as to the validity of the claim that parabens were actually present in the breast tumour tissue. This is based on the fact that parabens were detected in all the negative control samples. Indeed, one of the negative controls contained higher concentrations of parabens than 12 of the tissue samples; another negative control contained higher paraben concentrations than nine of the tissue samples. Most scientists would surely agree that to find a positive result from a negative control places serious doubt over the validity of the actual test samples. The presence of the parabens in the negative controls was ascribed to contamination, but it was assumed that the parabens detected in the tissue samples had there arrived systemically after application in a cosmetic product on the skin. The problem with this assumption is that the paraben concentrations in both controls and tissue samples were broadly similar and, moreover, the ratios of the different esters were also broadly similar. This strongly suggests that the parabens detected in the controls and the tissue samples came from the same source as it is difficult to understand how the parabens detected in the tissue samples could have passed through any part of the human body, avoiding any metabolic breakdown, and embedded themselves in breast tumour tissue. Additionally, the ratios of esters correspond to average usage. For example, 62% of the parabens detected were methylparaben, which would be expected from overall parabens usage in cosmetics. A further concern is based on the statement in the synopsis that parabens possess oestrogenic activity. This is partially qualified by later reference to the work of Routledge et al. [5], but could still easily be misinterpreted by the uninformed reader. The title of the paper by Routledge et al. uses the qualifying ‘some’, whereas the Pedersen et al. paper suggests that all parabens possess this activity. When one considers that the most potent oestrogen mimic among the parabens tested in vivo by Routledge et al. was butylparaben, and this was International Journal of Cosmetic Science, 2008, 30, 229–230

Amikacin reverse iontophoresis: Optimization of in vitro extraction

The aim of this work was to optimize amikacin reverse iontophoretic extraction across the skin in vitro, for non-invasive drug monitoring. Reverse iontophoresis experiments were performed using vertical diffusion cells. The lower chamber, simulating body fluids, contained amikacin bisulphate and acetaminophen, as marker for electroosmosis, while the upper chamber was filled with the appropriate extraction solution. The effect of concentration of amikacin in the dermal bathing solution and the effect of extraction solution composition and pH were studied. The results show that the extraction of amikacin was independent of pH and always in the anode-to-cathode direction, in agreement with the positive charge of the drug. The presence of amikacin in the bathing solution did not modify acetaminophen extraction at pH 4.0, while the extraction was reduced at pH 8.0. In conclusion, amikacin can be extracted across the skin in vitro by reverse iontophoresis. Owing to the charge of the molecule, extraction takes place at the cathode. Using acetaminophen as neutral marker, it was shown that amikacin can interact with the skin and alter its permselectivity at pH 8.0.

Synthesis, hydrolysis, and skin retention of amino acid esters of α-tocopherol

The aim of this work was to synthesize new pro-vitamins of alpha-tocopherol (VE) able to release another moiety such as an amino acid, in order to obtain a combined antioxidant and moisturizing effect upon topical application. The new derivatives were characterized and tested for sensitivity to chemical and enzymatic hydrolysis. Lipophilicity was estimated using Log capacity factor and skin retention was determined in vitro, using rabbit ear skin as barrier. Five molecules were synthesized using L-proline, L-serine, L-tyrosine, L-asparagine, and L-citrulline as amino acidic moiety. All pro-vitamins showed similar or lower lipophilicity than alpha-tocopheryl acetate (VEAc), taken as reference, and similar stability in aqueous solutions. All pro-vitamins showed to be sensitive to enzymatic hydrolysis. None of the pro-vitamins crossed the skin in significant amounts, whereas they accumulated into the skin, in both the dermis and the epidermis. They are more hydrophilic and more water-soluble than the currently used acetate.

A forecasting performance comparison of dynamic factor models based on static and dynamic methods

Abstract We present a comparison of the forecasting performances of three Dynamic Factor Models on a large monthly data panel of macroeconomic and financial time series for the UE economy. The first model relies on static principal-component and was introduced by Stock and Watson (2002a, b). The second is based on generalized principal components and it was introduced by Forni, Hallin, Lippi and Reichlin (2000, 2005). The last model has been recently proposed by Forni, Hallin, Lippi and Zaffaroni (2015, 2016). The data panel is split into two parts: the calibration sample, from February 1986 to December 2000, is used to select the most performing specification for each class of models in a in- sample environment, and the proper sample, from January 2001 to November 2015, is used to compare the performances of the selected models in an out-of-sample environment. The metholodogical approach is analogous to Forni, Giovannelli, Lippi and Soccorsi (2016), but also the size of the rolling window is empirically estimated in the calibration process to achieve more robustness. We find that, on the proper sample, the last model is the most performing for the Inflation. However, mixed evidencies appear over the proper sample for the Industrial Production.

Calibrating Dynamic Factor Models with Genetic Algorithms

In this work, we address the problem of calibrating dynamic factor models for macroeconomic forecasting. The variables upon which the forecasts are computed are the logarithm of the Industrial Production (IP) and the yearly change of the logarithm of the Consumer Price Index (CPI). Our purpose is to provide a contribution to the model identification by proposing a new kind of calibration of static and dynamic factor models. The innovative part of our work consists of building a genetic algorithm for calibrating three dynamic factor models. We first analyse a dataset of 176 EU macroeconomic and financial time series and then we conduct the same study on a dataset of 115 US macroeconomic and financial time series. In both studies, the employment of genetic algorithm in the calibration procedure produces very good results and more significant than those achieved in similar studies, such as [1, 2].