The paper is highly cited because the research centers on issues of current public concern, namely whether estrogenic chemicals are involved in the development and/or progression of breast cancer. The established impact of endocrine disruption on aquatic wildlife has demonstrated the potential for pollutant chemicals with estrogenic properties to also give rise to adverse effects on human health. However, progress has stalled in recent years over identification of sources of real-life human exposure which would allow for widespread and continuous exposure in an analogous way to that in which the aquatic species are exposed continuously through chemicals in the water in which they live. However, in the context of breast disease, there has been a realization that the application of chemical constituents of cosmetics applied to the underarm and breast area could satisfy the exposure issue in terms of widespread use and continuous direct dermal exposure if such chemicals could enter the breast in sufficient quantities [Harvey PW and Darbre PD, "Endocrine disrupters and human health," J Appl Toxicol 24: 167-176, 2004]. This paper described for the first time the measurement of parabens (alkyl esters of p-hydroxybenzoic acid) in the human breast, and parabens were already known to possess estrogenic properties and are used as preservatives in thousands of cosmetic, food, and pharmaceutical products to which the human population is exposed. It is thus possible that this may provide a potential first link between endocrine disruption and a human health problem.

The main impact of this paper has been simply in the detection of parabens in human tissues for the first time. It was assumed previously that although parabens were known to penetrate animal skin, they could not be expected to enter the human body. We used human breast tissue because we were specifically interested in whether parabens could enter the human breast. This adds parabens to the list of estrogenic chemicals which can be detected in the human breast. However, unlike other estrogenic chemicals found in the human breast, such as organochlorine agrochemicals and polychlorinated biphenyls, which enter as environmental pollutant chemicals, the parabens are additives to consumer products which could potentially be removed or replaced.

The significance of the paper lies in it being the first report of measurement of parabens in human tissues. This serves to demonstrate that if the human population is exposed to parabens through their addition as preservatives to consumer products, then they will enter the human body. The finding of parabens in human breast tumor tissue is of interest because parabens have previously been shown to possess estrogen-mimicking properties and estrogen is known to influence the incidence and progression of human breast cancer. However, it is also important to emphasize the limitations of this study in that it did not demonstrate any functional linkage between the presence of the parabens and development of breast cancer, and nor could it identify the source of the parabens from the thousands of consumer products to which these compounds are added.

For the past 23 years, my research interests have centered on estrogen regulation of breast cancer cell growth and it is from this background that I have begun to investigate whether there is any functional role for environmental estrogen-mimicking chemicals in breast cancer. The human population can be exposed to environmental estrogens through edible plant material (phytoestrogens), through the use of synthetic estrogens (e.g., the contraceptive pill, hormone replacement therapy), or through man-made pollutant estrogenic chemicals entering the diet via the food chain or applied dermally as cosmetic preparations. This paper is part of a research project to investigate whether the chemical constituents of cosmetics applied to the underarm and breast area may play a role in the incidence and progression of human breast cancer. These cosmetics are applied with increasing frequency by women and men across the globe and are being used by ever-younger children and babies. They are left on the skin, allowing for accumulation and continuous exposure. The challenge of this research is to identify the mechanism of action of such a wide range of chemical constituents and to measure the levels of the different components entering the human breast. An important future step will be to investigate any potential synergy between the different chemicals in the formulations and with other environmental chemicals especially those with estrogenic properties and known to enter the human breast from diet such as the organochlorine agrochemicals and the polychlorinated biphenyls. With regard to the parabens specifically, previous work by us and others had shown that parabens could mimic the action of estrogen in both in vitro and in vivo assays, and parabens could be readily absorbed through the skin of animals as intact esters [reviewed in Harvey PW and Darbre PD, " Endocrine disrupters and human health," J. Appl. Toxicol. 24: 167-176, 2004]. However, the question remained as to whether parabens could enter the human body intact from the long-term, low-dose levels to which humans are exposed through consumer products. This was the first paper to demonstrate measurable levels of parabens in the form of intact esters in the human body, and although the study could not identify the source of the parabens measured, it did establish the existence of intact parabens in the human breast. The project was only made possible through the collaboration with colleagues at the Edinburgh Breast Unit (for tissue supply and extractions) and at the Veterinary Laboratories Agency in Weybridge (for HPLC-MS/MS measurement). Clearly, further research will now be needed to expand this work to study larger populations, other body tissues, and to identify the source of exposure.