Skincare aisles are stocked with an endless array of anti-wrinkle formulas. The packaging is different, the claims vary, but most have one thing in common: If you read the ingredients, you will invariably find retinoids -- derivatives of Vitamin A.
What are these wrinkle-erasing elixirs? We’re here to explain how they work, what they’re in and why one derivative in particular -- retinyl palmitate -- is accused of causing skin cancer.
Retin-A, in the beginning
Vitamin A is essential for healthy eyes and skin. It exists naturally in liver, butter and eggs; and its precursor, beta-carotene, is in colorful vegetables such as carrots, sweet potatoes and spinach. In order for the skin to benefit from Vitamin A, the body converts it to retinoic acid.
Several decades ago, this connection led dermatologists to pinpoint topical retinoids that effectively break down into retinoic acid as effective treatments for various skin ailments.
In the late 1960s, Albert Kligman, M.D., Ph.D., a dermatologist at the University of Pennsylvania, started testing a Vitamin A derivative called tretinoin on acne patients. By 1973, Kligman patented his formula for Retin-A, the first-ever effective acne treatment.
About twelve years later, Kligman and Leyden noticed Retin-A’s other lucrative effects: tretinoin patients had few wrinkles and smooth skintones. Kligman secured another set of patents, and the rest of the cosmetic industry soon followed with an abundance of anti-wrinkle retinoid treatments.
“Retinoids prevent wrinkles,” says Miami dermatologist and retinoid expert Leslie Baumann, M.D., “And, they are the only topical product that gets rid of wrinkles you already have.”
How to erase a wrinkle
Retinoids bind to corresponding receptors in the skin. This peels off the top layer, which evens skin tone, and thickens the layers below, which smoothes out wrinkles. Retinoids also boost collagen, a protein that keeps the skin firm and springy, by blocking the genes that cause it to break down and increasing other gene activity responsible for its production.
Retinoids and sunlight
Retinoids degrade in light, which is why most dermatologists recommend nighttime application.
The discovery that retinoids were photosensitive was, in part, pure luck. James Leyden, M.D., Kligman’s colleague, tells YouBeauty that their team ran out of brown test bottles during the experiments and had to put some tretinoin mixtures in clear bottles. The mixtures in the clear containers stopped working sooner than their counterparts, showing that tretinoin was unstable when exposed to light.
Contrary to Retin-A lore, however, the drug does not increase the skin’s photosensitivity (sensitivity to light) in the strictest sense. Technically, photosensitivity happens when a molecule absorbs light and produces a chemical that damages the skin.
With Retin-A, this is not the case. Instead, tretinoin molecules make the skin more sensitive to light by thinning the outer layer of skin by about a third, the equivalent of lowering its natural SPF by a few points. This means that the skin is more sensitive to sunburn. But, it does not mean that Retin-A produces harmful chemicals in sunlight.
“It’s true that if you used Retin-A and you were a lifeguard in the middle of July in Ocean City, NJ, that would be stupid,” says Leyden, the Retin-A researcher, “But if you apply it, an hour or so passes and then you go out and get in your car, that is not a problem.”
Retin-A vs. retinol
Today, the Retin-A patents have expired, allowing over-the-counter brands such as Renova, Refissa and Atralin to come to market. All of these, like Retin-A, cause skin irritation in some people. Generics are also available but have less-effective moisturizer bases, according to Baumann.
Other non-prescription anti-wrinkle creams utilize retinol, a milder option, which readily converts to retinoic acid in the skin. Retinol, however, is very unstable in heat, light and air -- more so than tretinoin -- rendering it useless if overexposed. Aluminum tubes with narrow mouths offer the best protection, such as those used in retinol products by Roc, Neutrogena and Philosophy.
Synthetic retinoids, Adapalene and Tazarotene, used in Differin and EpiDuo, are chemically different than natural retinoids, but are just as effective. Synthetics are also less reactive to sunlight and gentler on the skin.
The least effective retinoids, Baumann says, include retinal, which is naturally occurring, and retinyl esters. One retinyl ester -- retinyl palmitate -- is at the heart of a debate.
The retinyl palmitate controversy
In 2000, the National Toxicology Program, which is run by the U.S. Department of Health and Human Services, announced that it would study how retinyl-palmitate-treated skin reacted to sunlight based on the “increasingly widespread use” of the compound in cosmetic products, including sunscreens.
The compound is not an essential sunscreen ingredient, says Baumann, who suggests that manufacturers put retinyl palmitate in sunscreens as a marketing tool in order to claim anti-aging benefits even though the compound is among the least-effective retinoids for fighting wrinkles.
NTP scientists tested retinyl palmitate on SKH-1 mice, a hairless strain commonly used as a model in skin cancer research. One group was treated with a plain cream (that did not contain sunscreen) for control, a second with the same cream mixed with a small amount of retinyl palmitate, and the third with the cream mixed with retinoic acid (another A derivative). All were exposed to the same amount of simulated sunlight.
The NTP published preliminary results in 2010 -- which were approved by a peer-review panel earlier this year -- showing that the mice swabbed with retinyl palmitate had a higher rate of skin tumors than both other groups. The cream-sans-retinoid group, however, showed a high rate of skin lesions. The study sparked an argument, which continues today, over the safety of sunscreens containing retinyl palmitate.
In one corner is the Environmental Working Group, a nonprofit consumer watchdog. Shortly after the N.T.P. made their preliminary results public, the E.W.G. put out a warning that sunscreens containing Vitamin A posed a cancer risk in humans (in an interview with YouBeauty, the E.W.G. amended that to retinyl palmitate; the N.T.P. did not test Vitamin A).
According to the E.W.G., 41 percent of sunscreen products with SPF 30 or higher contain retinyl palmitate, which they say is a significant increase from five years ago. The group recommends that consumers avoid sunscreen products containing the compound, and calls for better regulation.
“This is one of the high-profile examples of why the F.D.A. is asleep at the wheel in terms of regulating cosmetic safety,” says senior researcher Sonya Lunder. “It also shows how quickly that industry can shift.”
On the other side is a collection of cosmetic industry representatives and dermatologists, including some with financial ties to cosmetic companies. Their critiques: the control cream alone showed an increase in tumor rates (albeit not as high as the retinyl palmitate cream), when used in sunscreen an SPF would by nature negate any problems retinyl palmitate might cause, animal research does not perfectly extrapolate to humans, and SKH-1 mice are known to be particularly sensitive to sunlight.
Also, the control cream contained a carcinogen, which led to confusion over the independent effects of retinyl palmitate.
To retinyl palmitate or not to retinyl palmitate
Santosh Katiyar, Ph.D., a professor of dermatology at the University of Alabama School of Medicine who has studied the photocarcinogenesis for two decades, says at least two of the NTP study critiques are inaccurate.
“The SKH-1 hairless mice is the best mouse model available for this purpose,” he says, “And, it is not difficult to extrapolate data from mouse model to humans because of similarity in their physiological systems.” A recent study in the journal Photochemistry and Photobiology agrees, concluding that the skin of SKH-1 mice exposed to UV light responds similarly to human skin. And according to Massachusetts-based Charles River Laboratories, which breed the mice, SKH-1 are “the closest mimic of the human in an animal model.”
Research on the effect of retinyl palmitates in sunscreens is, for now, paltry. One recent study by dermatologists from the University of São Paulo in Brazil showed mice treated with a sunscreen containing retinyl palmitate still showed thinning of the skin. Adding a photostabilizer (which slows the breakdown of SPF in chemical sunscreens) to the sunscreen-retinyl palmitate cream improved protection against UV light. The F.D.A., for its part, is not ready to release an official statement until the N.T.P. finishes studies “to clarify the noted effect of retinyl palmitate.”
So, what to make of all this? Until the N.T.P. and other parties conduct more tests -- specifically, experiments with neutral creams and sunscreens -- it is not possible to draw a firm conclusion.
“I tell my patients to avoid products in the day with retinyl palmitate, if it is high on the ingredient list,” adds Baumann, referring to the fact that ingredients listed near the top of a label typically appear in higher concentrations than those listed farther down.
“I do not feel that there is enough evidence to prove that it causes skin cancer. But, then again, can you give me one good reason to use it? I cannot think of any.”