Parabens have been used as preservatives since the 1920s. Chemically, parabens have a simple structure. They consist of a six-member carbon ring with a hydroxyl group on one side (-OH) of the ring and a side chain called an alkyl ester on the opposite side of the ring. The side chains can be of varying lengths. One of the most widely quoted sources of information on the use of, exposure to, and safety of parabens was published in 1984 in a report authored by Elder.¹ This report estimated that parabens were used in over 13,200 different cosmetic products. Parabens are colorless and odorless. They also have activity against a wide range of bacteria. They are less active against fungi and, therefore, are usually combined with other biocides such as formaldehyde releasers, isothiazolinones, or phenoxyethanol to provide a broader antiseptic action.

Products Commonly Containing Paraben Preservatives

Cosmetics
Foundations, powders, concealers, eye makeup (liners, shadows, mascara), facial makeup (blushes), bronzes, makeup removers, lipstick, quick-dry nail products

Pharmaceutical Products
Topical dermatological medications, eye, ear and nose drops, rectal and vaginal medications, bandages, parenteral products, including antibiotics, corticosteroids, local anesthetics, radiopharmaceuticals, vitamins, antihypertensives, diuretics, insulin, heparin, and chemotherapeutic agents

Personal Care Products
Moisturizing lotions and creams, dentifrices, sunscreens, cleansers and other skin care products, antiperspirants and deodorants, soaps, including liquid hand soap and toothpastes, shampoos and conditioners, colognes, and perfumes

Food Products (E210-219)
Marinated fish products, salad dressings, mayonnaise, mustard, spiced sauces, processed vegetables, frozen dairy products, jams and jellies, soft drinks and fruit juices, baked goods, and candies

Industrial Products
Parabens are used industrially in oils, fats, shoe polishes, textiles, and glues.

The Dangers of Parabens

Studies demonstrate the health risks of parabens. Some scientists have raised concerns that further assessment of parabens may be needed. This is based on recent evidence from scientific studies indicating that several types of parabens can bind to the estrogen receptor and can cause estrogen-like responses when tested in laboratory animals or in a variety of tissue culture assays.² Parabens produced a positive uterotrophic response in vivo and also damaged the late stages of spermatogenesis, altered proportion of pups born alive, and affected body weight of offspring. They reduced the number of sperm in the epididymis and reduced the sperm motile activity in male offspring. Parabens could compete with [3H] 17beta-estradiol for binding to the estrogen receptor. The proliferation of two estrogen-dependent cell lines MCF-7 and ZR-75-1 could be increased by parabens. They also increased expression of both transfected and endogenous estrogen-regulated genes in MCF-7 cells. The studies showed parabens were weakly estrogenic.³

The following studies of estrogenic activity/antispermatogenic potential of parabens indicated a possible relationship between paraben exposure and breast cancer and/or male reproductive function: Dr. S. Oishi of the Department of Toxicology, Tokyo Metropolitan Research Laboratory of Public Health, Japan reported that exposure of postweaning rats and mice to butylparaben or propylparaben (but not methylparaben or ethylparaben) adversely affected the secretion of testosterone and the function of the male reproductive system.⁴ British researcher Dr. Philippa Darbre and colleagues at the University of Reading⁵ proposed that parabens may contribute to the increasing incidence of breast cancer. Darbre et al. carried out tests on 20 samples of human breast tissue taken from patients undergoing surgery at the Edinburgh Breast Unit in Scotland, UK. The study by P. Darbre and colleagues was conducted to assess whether any of the six parabens commonly used in consumer products in Europe could be detected in human breast tumors. The parabens studied were methylparaben, ethylparaben, propylparaben, isobutylparaben, butylparaben, and benzylparaben.

The Scottish study is the first report of the detection of parabens in human breast tumors. It enabled identification and measurement of mean concentrations of individual parabens in samples of 20 human breast tumors. Comparison of individual parabens showed that methylparaben was present at the highest level (with a mean value of 12.8 +/- 2.2 ng x g [-1] tissue) and represents 62% of the total parabens recovered in the extractions. This investigation did demonstrate that five of the six parabens widely used in consumer products could be detected intact (not changed or metabolized) in human tissues. The study did not, however, make any attempt to find out the source of the parabens. It is not known if the major exposure was due to the parabens from food or via topical application of a certain type or a variety of personal care products. Since 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.

In the sixteenth century, Paracelsus said, "It is the dose that makes the poison." However, over a lifetime, with daily use of products containing parabens, we don't actually know what the cumulative dose really is. Future work will need to address the extent to which parabens can accumulate in hormonally sensitive tissues and also the extent to which their weak oestrogenic activity can add to the more general environmental oestrogen problem.

Allergenicity of Parabens

Type IV Delayed-Type Hypersensitivity Reactions to Topical and Ingested Parabens in Orally Administered Products
Numerous individual reports describing cases of contact dermatitis as a result of contact with parabens in topical products – such as reactions to facial cosmetic products and formulations, gel-like toy products, ultrasound gel, topical creams, etc. – have been published. Occupational cases of paraben contact dermatitis (among cooks and food handlers with hand dermatitis caused by paraben-containing foods) have also been reported. Allergic contact dermatitis has most commonly been described when paraben-containing products are used on damaged skin. In a phenomenon known as the "paraben paradox" by Fisher,⁶ inflamed skin reacts to parabens whereas intact skin does not. This concept is important, because patch tests may produce false-negative findings in patients who are truly sensitive to parabens. There are a few reports of a systemic allergic contact dermatitis presenting as a generalized eczematous eruption after ingestion of paraben-containing medications or foods.

Type I Immediate Hypersensitivity Reactions to Topical and Parenteral Parabens
The same paraben compounds that cause delayed-type reactions can also cause type I immediate reactions such as contact urticaria.⁷ Several cases of immediate hypersensitivity reactions (including bronchospasm, pruritus, localized angioedema, and generalized dermatitis) to parenterally administered compounds containing parabens have been reported.¹

Type IV Hypersensitivity Reactions to Parenteral Parabens
Fine and Dingman reported one case of generalized eczematous dermatitis following suction-assisted lipectomy when a local anesthetic containing methylparaben was used.⁸

Patch Testing with Paraben Mix
Two or more paraben esters are often found in a single product, so it is useful to test paraben sensitivity with paraben mix, as there is a high incidence of cross-reactions between the esters. Paraben mix is a mixture of five different paraben esters: methyl-, ethyl-, propyl-, butyl-, and benzyl-parahydroxybenzoic acids. Paraben-mix sensitivity produces classic allergic contact dermatitis reactions. Sometimes, the reactions may be seen as a flare or spread of an existing treated rash. It appears that repeated applications of relatively low concentrations of parabens in medications and cosmetics may lead to sensitivity. Paraben-mix allergy is diagnosed from the clinical history and by performing special allergy tests, i.e., patch tests. Patch testing with 15% paraben mix in petrolatum (three percent each of methyl-, ethyl-, propyl-, butyl-, and benzyl-parahydroxybenzoic acids) is used. This mix caused ACD in one percent of patients patch-tested by the North American Contact Dermatitis Group (NACDG).⁹

Cross Reactions
The "para" group of antigens (para-aminobenzoic acid [PABA] esters, paraphenylenediamine) are frequent sensitizers and consist of chemicals with a free amino group in the para position of a benzene ring. A debate exists about the cross-reactivity of parabens and the "para" group, because parabens have a hydroxyl group instead of an amino group in the para position. Although PABA itself does not cross-react with parabens, the esters of PABA may show cross-reactivity.⁷

Parabens as Urinary Biomarkers of Exposure in Humans
A team from the Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, Georgia, has now provided the field with new biomarkers that could help researchers document exposures to parabens.¹⁰ Until now, the only biomarker used for human paraben exposure was p-hydroxybenzoic acid in urine. However, that metabolite is produced by the hydrolysis of all the various paraben compounds, so it is nonspecific to individual parabens, which vary widely in estrogenic bioactivity.

Ye et al. measured the presence of free and conjugated parent parabens in urine to determine their suitability to be biomarkers of human exposures. They analyzed the urinary concentrations of methyl, ethyl, n-propyl, butyl (n- and iso-), and benzyl parabens in 100 human adults with no known industrial exposure to the compounds. The results appear to support the viability of those measures as biomarkers of exposure. Methyl and n-propyl parabens, the parabens most commonly used in cosmetics and foods, were found at the highest median concentrations in almost all the samples—99% contained the former and 96% the latter. The authors say this could result from the widespread use of these compounds; from differences in the absorption, distribution, metabolism, and excretion of the various parabens; or from a combination of both factors. Other parent compounds, such as ethyl and butyl paraben, appeared in more than half of the samples. Regardless of the reason for such high frequencies of detection, the researchers say their results suggest that urinary parabens and their conjugates could be valid biomarkers of exposure to these chemicals. The detection and measurement methodologies used by Ye et al. could help investigators as they seek to characterize the potential health risks associated with exposure to the individual paraben compounds.¹0

1) Elder RL. Final report on the safety assessment of methylparaben, ethylparaben, propylparaben and butylparaben. Journal of the American College of Toxicology. 1984; 3:147-209.
2) Endocrine Disruption Bibliographies. Available at: http://envirocancer.cornell.edu/Bibliography/cENDOCRINE.cfm. Accessed August 27, 2007.
3) Ge JH, Chang B. Estrogenic activities of parabens. Wei Sheng Yan Jiu. 2006 Sep;35(5):650-2.
4) Oishi S. Effects of butyl paraben on the male reproductive system in mice. Arch Toxicol. 2002;76(7):423-429.
5) Darbre PD, Aljarrah A, Miller WR, Coldham NG, Sauer MJ, Pope GS. Concentrations of parabens in human breast tumors. Journal of Applied Toxicology. 2004; 24: 5-13.
6) Fisher AA. The paraben paradoxes. Cutis. 1973;12:830-1.
7) Cashman AL, Warshaw EM. Parabens: a review of epidemiology, structure, allergenicity, and hormonal properties. Dermatitis. 2005;16(2):57-66.
8) Fine PG, Dingman DL. Hypersensitivity dermatitis following suction-assisted lipectomy: a complication of local anesthetic. Ann Plast Surg. 1988;20:573-5.
9) Pratt MD, Belsito DV, DeLeo, et al. North American Contact Dermatitis Group patch-test results, 2000-2002 study period. Dermatitis. 2004;15(4):1-8.
10) Ye X, Bishop AM, Reidy JA, Needham LL, Calafat AM. Parabens as urinary biomarkers of exposure in humans. Environmental Health Perspectives. December 2006; 114 (12):1843-1846.