[Music] Welcome to Ask the Investigator, brought to you by the Journal of Drugs and Dermatology. The JDD podcast illuminates timely scientific content through thoughtful discussion with top dermatology authors. [Music] Subscribe to the Journal of Drugs and Dermatology at JDDOnline.com to browse the current issue in evidence-based peer-reviewed archives. [Music] Welcome back to the Lace episode of the JDD podcast. I'm your host, Dr. Adam Friedman, Professor and Chair of Dermatology at the GW School of Medicine and Health Sciences. This podcast is funded by Kenview. Our guest today is the amazing Dr. Jay Nash. Dr. Nash is a research fellow at the Proctor and Gamble Company. He has conducted multiple in-depth, toxicological evaluations of active ingredients and products and communicated such results with regulators across the world, including the FDA, the Madrera Mentoral Protection Agency, the European Commission and their Expert Review Committee, and European Chemicals Agency. Dr. Nash's expertise in dermal toxicology with a specialization in photobiology and photo-toxicology, having extensive knowledge of in vitro, animal and human models and efficacy testing of sunscreen products. You can get a sense of what we're going to be talking about it clearly. Dr. Nash has chaired and served on pharmacological and toxicological working groups at multiple trade associations, including the American Cleaning Institute, Consumer Healthcare Products Association, Personal Care Products Council, and the Pharmaceutical Research Manufacturers Association. He was the chair of the PCPC UV filter Clinical Preclinical Safety Consortium and is currently co-chair of the International Collaboration on Cosmetic Safety Sunscreen Working Group. Welcome to the podcast, Dr. Nash. Thank you. It's a pleasure to be here and it's an honor to have this opportunity to talk to you, Adam. Yeah, I'm really excited. So we're going to be speaking about a recent paper you publish in Critical Reviews and Toxicology, entitled "Mode of Action Approach Supports a Lack of Carcerogenic Potential of Six Organic UV Filters." Now, so long as someone hasn't been living under some very dense structure, there are no question has been an unparalleled rise in consumer and ATP skepticism around sunscreen safety, often driven by content on social media where misconceptions about cancer risk, for example, are fruitful and multiplying out of control. So having some solid evidence and of course a healthy discussion about that I think is sorely needed and that's why you're here with me today. So to try to jump right in and maybe I kind of already kind of led with a, an answer/question, a prompted you and your co-authors to undertake this review on organic UV filters and carcerogenicity. Yeah, so this has been building for some time. So I don't want to go back too far in history, but I think there are a couple of important dates. One of those is 2016. 2016 there was a coalition of sunscreen, active ingredients, also known as UV filters, that ask the FDA, "Look, we want to try to get some new filters in. What is the mechanism?" And then went through Congress, Congress said to FDA, "You're going to have to make a decision here and we'll give you four years to do that in." And during that four years there were several meetings with industry and manufacturers. And during the course of that the agency did what they do, which is to review the data that exists for the filters that people wanted to introduce, new filters, and the existing filters. And they did some research of their own. I know in that research of their own they found that in fact some of these UV filters do penetrate into the skin. So during the course of this they had questions related to the safety of the UV filters. So some screens in the US are drug products. And drug products, in particular the active ingredients, undergo extensive testing in order to demonstrate the safety of these materials. And so the FDA said, "Hey, look, you know, sunscreens are increasing in use." And they're found in multiple types of products. So not just your recreational beach product, but also in facial moisturizers, in color cosmetics. And so we believe that there is more data needed for us to determine grass status. Now grass is generally recognized as safe and effective. And it's a means of saying these UV filters can be used in any product type at certain concentrations. And we will not need to know what the form of that is in order for you to sell that product. So that's the agreement we as manufacturers have with the agency. And so the agency said, "Oh, by the way, you know, we think that you need carcinogenicity testing, developmental reproductive toxicity testing, human pharmacokinetic testing, toxicokinetic testing, and rats. All of these things may not make much sense to most people, but in the world of safety, these are the biggest type of studies that are needed." So this was the prompting. And that happened in 2018 and then 2019, 2020. COVID came in to be. There was a new form of the monograph called the CARES Act that was passed. And during the course of that, the agency continued to ask the questions of industry, what about the safety of these UV filters? And industry in the meantime, had created a working group. And that working group was done through the Personal Care Products Council or PCPC. And we connected with nine external experts to help us think about these UV filters, think about the safety of them, and think about the testing that the agency was asking for. That was for a moment because I. Yeah, no, no, that, honestly, that was the clearest kind of historical recount and explanation, because you actually answered my second question for you, which is, "The why did the FDA request to all this?" And I think a lot of people don't recognize that sunscreens in the US are looked at as drugs, even though we may think of them as cosmetics or something under the umbrella of something over the counter. But because they're regarded as drugs, the regulation and the requirements from a safety perspective are going to be more onerous. And I love that you're kind of going through time because you're right. Obviously, what's going on around us can have a big impact on the speed with which certain requirements are really executed. The resource is available to even acquiesce to some of these requirements. Certainly, can all be directed by what's going on in the world, like, "Oh, I don't know a global pandemic." One question after you, why was there such a focus on the 6 UV filters that even you looked at in your paper? Why would these have a giant target on them? Yeah, that's an excellent question. So amongst the, what's called the monograph UV filters, in 1992, there were 22 of them. In 2012, there were about 16 of them. Then in 2020, we're down down to really 12 plus the two inorganics, which is titanium and zinc. Titanium and zinc were considered grass. They were considered grass because they don't penetrate through the skin. So they were considered to be not systemically available. The remaining 12 of those 12, there are seven that are commonly found not only in products in the US, but products throughout the world. Remember, to some extent, UV filters, they tend to be more commodity type of ingredients, but if you have an SPF 15 or an SPF 30 and you have four different UV filters, you can
Well, it doesn't matter what those are. It matters in terms of combination, but it doesn't matter if they're able to bend zone, oxy, oxy, oxy, bend zone, and sulazole. They all have different reasons for being there, but an SPF 30 is an SPF 30, whether it's product A or product B. If that makes sense in terms of, you know, whether I have to have these ingredients, they're put there for reasons. For example, in sulazole, it's a water soluble sunscreen. Certainly wouldn't want a water soluble sunscreen, and a beach product that you hope is waterproof. What would hope, right? You wouldn't hope, but those six happen to be the most commonly used. Again, in a global context. So we focused on those six, because really, if you only have products that had zinc and titanium, you would be doing a big disservice to your patients, to our consumers, because products was titanium and zinc. Again, I'm all in favor of those type of products, and I've supported both titanium and zinc, oxy, as active ingredients. But they are not as efficient as the organics. In other words, if you think about what a UV filter does, it's absorbing photons coming from the sun, and those photons are high energy UV, and the efficiency at which they do that, or it's very different. So I only need 3% of able benzoin to achieve a much greater efficacy than if I have 3% of zinc, or 3% of titanium dioxide. So that efficiency is important. I'm just so glad you brought that up. That is such an important point, because I think there is this narrative of, oh, well, we don't know if there's any of these organic filters. They're not safe, which is certainly not validated by the literature. But don't worry about that. Just use zinc or titanium. It's all the same. And there are many reasons why that's not true. I think certainly from a practical standpoint, the ability to apply zinc, oxy, or titanium, acys doesn't always line up with a product that needs to be applied multiple times a day to exposed areas. But even to your point, the efficiency as a UV filter, yes, they can meet muster based on the expectation to protect against ultraviolet radiation, that the amount needed to do so, and then the resulting product. And I know there are some ways to try to compensate for that with nano-scaled or micro-scaled particles, which I am a big fan of. At the end of the day, though, I agree that had to be said they are not as efficient as our chemical sunscreens, but we are really being handcuffed based on the regulatory space, but also the misinformation that's being kind of pushed out there. And also, I just want to highlight, because we can be mentioning these six UV filters. Could you share with us the six filters that you guys were really focusing on your paper? We're going to dive into your paper in just a moment. Yes, absolutely. So, Aval Benzone and Sulazol, Homosalate, Octanoxate, Octocryline and Octosalislate. So those are the six UV filters. Two of them are Sulazolate based, two of them are Cinemat based, and then two of them Aval Benzone and Sulazol are not of a class. Like the other two. So, to some extent, there are six independent, if you will, UV filters. Now, they have different absorbance profiles, and you probably know quite well, Adam, that Aval Benzone is a long wavelength UVA filter, critically important in the context of broad spectrum, and fundamental to photo protection for everyone. We want broad spectrum protection for all consumers, because, you know, again, that spectrum, both short wavelength UVB and long wavelength UVA, reducing the dose of those, of that energy is critical for skin health. From your mouth to everyone's ears, completely agree. And we are so limited, especially when it comes to the UVA side of things in terms of really protecting from what I think of like the deeper, but also the silent injury given that UVA does not induce air theme like UVB, but it certainly can. Again, you blast some of the enough UVA, you will see air theme, but it has an extraordinary impact on dermal structures, on collagen, alastin, which is why it's implicated to a greater extent in photo aging than even UVB. Now, getting it to your paper, which I really love, you guys proposed this mode of action framework. Instead of the traditional kind of two year, rodent, carcinogenicity studies, which you mentioned earlier, can you explain what is this M.O.A approach, and why may it be more relevant for human risk assessment? Yes, absolutely. So let me take a moment just to talk about the two year bioassay. The two year bioassay is a standard cancer determining assay, generally speaking, it's either rats or mice. And it's two years because that's the lifetime of those small rodents. And it's been used since the beginning in the 1950s, but then in the 1970s was more or less taken up as a standard way of assessing drugs. So largely in the pharmaceutical, but also other other chemicals. Two years is a long time. That's just treating the animals because it's actually a year before that and a year after to do the prep work for treating and then the assessment thereafter. So you're really talking about four to five years for a bioassay. And so historically, this has been something that's been done. Now, the good news is as said, a negative in a bioassay is a negative. In other words, if you don't see anything, then generally speaking in humans, you won't see anything. So that's good news. But the relevance to humans, particularly for ingredients or chemicals that don't damage directly DNA is really very low. In fact, it's about 20% if you have a positive in a rat bioassay for out of five times, it's not going to be relevant to humans. But that's a relatively amazing district. So, so let me set the stage a little bit more. You have ingredients, UV filters, the six that we're talking about that have been used by humans for over 40 years. And this is 50 years of human exposure. And the request to do a two year bioassay has very little relevance to the human situation. And by the way, you'd learn a lot about the rat, but you would learn a little about the human. This seems like nonsense, but that's truly the case. So together with these nine, I mean real experts, you know, Sam Cohen is an individual who really has for years been talking about the bioassay and really the lack of human relevance. He was, he did a lot of work on saccharin and it's done a lot of work on a renal cancer. One of the world's most most cited experts in cancer Tony Ciali, Alan Bubas, David Jacobs and Cram Rita, Shoney, Thomas Rosal, Gary Williams, Nord, Norm Kovitsky, Fred Gingrich, all of these guys are all of them are, you know, world class. So we assembled them as a panel to help us come up with an approach that we could take for these UV filters again, which have decades of human exposure. And what we came up with was a mode of action. So let's talk about that mode of action for a minute. And I'll go through each one of these. And Adam, I can stop for each one and if you want to ask questions or I can just go through all four of them. You are on a very passionate role, my friend. I'm loving this. Yeah, I
That's, that's, that's loving. It's right. You did a great job kind of laying the scene of what has been done to date and why that may not necessarily translate to the human condition. And yeah, I think the best thing, let's go through those kind of main, uh, cross-region and categories, the MOAs that you guys looked at, specifically to really translate the data we have or the data we're going to generate to then understand the clinical relevance of that. So go for it. Okay. The first is DNA reactivity. And this is something that many people know about. And that is something called genotoxicity. So does the chemical interact with DNA and does it damage DNA? And for years, there have been tests that have been developed, uh, aims. Lots of people know Bruce Aims. He was very famous, developed the aims assay for direct DNA damage. And there are other assays that have come along since then, uh, that really determine what is the DNA reactivity of, of, of these, uh, these materials. And there's also not just the parent, but also metabolites of, of those. Uh, and so there are metabolic, uh, processes that are built into assess, uh, that possibility of, uh, DNA reactivity. So that's, that's the first mode of action. So let's suppose and what we did in looking at these, uh, was to look at the number of assays that have been done in the genotoxicity and, and it's pretty extensive for each one of these. And none of them are genotoxic. Well, let me just stop for a moment and repeat that because it's so, uh, uh, uh, make sure everyone's listening. None of them are genotoxic. Yeah. So none of them damage DNA and hurt you in the bleachers. I'm happy that they're, that they're listening. They're paying attention. I, I mean, you mentioned it at the beginning. I sometimes tell people I'm, I know so much about the subject and very few people really care about it. So I feel like I know a lot about the naked rat. No, or, or some caterpillar, uh, um, but, uh, okay, we're both. You must be really fun at parties. That sounds great. Great, great drinking conversations about the naked rats. Well, uh, so, so DNA reactivity, no genotoxicity. The next one is immune suppression and Adam, I, I know that you probably see, uh, patients who have had organ transplants who are on immunosuppression and many of them, many, many develop skin cancers. Many of them develop solid organ cancers. No suppression is one of the mechanisms for cancer inducing, uh, compounds. Interestingly, the rat bioassay doesn't really detect immunosuppressants as causing cancer. Yep. So the, another reason to say, what is this, uh, um, is this really important or is this really necessary or relevant to humans? If DNA reactivity, immunosuppression, then endocrine affects and specifically estrogen. So you know the example of, uh, breast cancer, uh, it can be estrogen, a driven, uh, and it can be initiated, uh, vis-a-vis estrogen. Uh, and so, uh, do, do, does a chemical or does a, uh, uh, a UV filter have estrogenic activity? Can it mimic estrogen, uh, in the human? And then the fourth is, uh, cytotoxicity and regenerative cell proliferation. So that's a bit of a mouthful, but, uh, think about tumor growth. Tumors are cells that are basically dividing too much. They're, they're overgrowing. But some of that is initiated through cell death leading to regenerative cell proliferation. So those are mechanisms. Those four modes of action are, are the known modes of action for human cancers. So we ask ourselves, okay, for these six UV filters, what do they fall out in these modes of action? But what is the data, uh, that supports, uh, the DNA reactivity, immune suppression, endocrine, estrogen effects, and cytotoxicity. And going through the data because one of the, one of the little known and understood aspects of these UV filters is, you know, it's not like they don't have any data. They do have data. A lot of it's older data. Like I said, you take a chemical that's been used for 50 years. Would you really expect to define a modern protocol driven, you know, GLP type of study? Some of them do have those, by the way. But often there's a lot of data that was developed before that. That doesn't make it scientifically irrelevant. I have to say in some people's minds, I think that they look at it slightly skeptically. But at the same time, when you have the vast amount of data that exists for these, uh, and again, each one of them separate, some have more, some have less. But when you look at the modes of action, none of these six UV filters are, um, are yes in activating those modes of action. So our argument has been, look, they don't have the mode of action from a cancer development standpoint in a human context. And then the second piece, if you're asking, you're in my mind, yes, go for it. The second piece is exposure, you know, and we talked about that a little bit in the beginning. I mentioned that the agency, uh, the FDA, that is, is concerned because, uh, you know, a lot of UV filters are showing up not only in sunscreen products, uh, you know, proper recreational type products, but also in facial moisturizers and foundations and lipsticks. So there, there, there certainly are more present than they were 50 years ago. So we need to take that into consideration. And by the way, the agency did some really remarkable work, uh, looking at what they call maximal usage trial. It's abbreviated must, uh, M-U-S-T. And that maximal usage trial basically showed that, uh, the internal dose, that is the concentration in the blood, uh, was in the nanomolar range. Now Adam, I know you're really familiar with nanotechnology. I know that. It's an extensive experience. What I like to do is to try to explain to people, what does nanomine? Because nanos just a word like micro and everyone kind of then goes to the next place. It's an iPod, right? Stop it. It's an iPod, that's right. But, but I like to put it in the, in the, in the, uh, in the category of time because I think people understand time. So if I'm talking about one part per billion, so a nanomonano gram, I'm talking about one second in 33 years, one second in 33 years. If I'm talking about a microgram, I'm talking about one second in 11.3 days. So think about how micrograms and nanograms are oftentimes, oh, I have a nanogram, I have a microgram. Okay. Yeah. They're different, but that difference is extraordinary. The difference between a millionaire and a billionaire is, is extraordinary. Pretty big deal. Yeah. Oh. Again, I think it helps to, for people to wrap their mind around what is a nanogram, uh, in a, in a human, uh, and what does that mean in terms of the bio activation of these materials? And so we looked at the cell-based activation and all of these materials activate cells in the micro, more microgram range. almost a hundred to a thousand
And more and more different than what's measured under the most aggressive exposure in humans. This is really important when it comes to the risk evaluation. And oftentimes what's missed when people talk about endocrine disruption, endocrine effects. Yeah, they're important and they can occur. You can see some endocrine effects with these materials. But they happen at concentrations that are 100 to 1000 times greater than what you can measure in a human. And I think you just scripted one of the responses my colleagues can share when patients come in, concerned. And you know, I knew at the very beginning it was a huge must to talk about the must studies. While maybe the general public, the medical community is not familiar with a lot of the safety data, no doubt the JAMA publications made it across their desk because that was extremely purposeful. And one of the things I would say to my colleagues is that the purpose of these was to show I can do it, right? Like they were able to detect animal or concentrations in the human system, which is certainly a tremendous feat. By no means did they correlate or even prove any causality of finding those animal or concentrations, they just were able to show it was there. But that data unfortunately was the muse, the stimulus for a lot of misinformation being that, oh, it's there. So clearly that relates to in the context of our conversation, cancer. The other thing that's so important, those must studies did not emulate real life. They did SharePoint optimal or unrealistic use of sunscreen. So there's no one puts on the amount that they really forced on the subjects during the course of these studies. So I think that the application in these trials were not realistic to daily use. But to your point, I think the most important point is that the levels detected were off the logarithmic scale lower than what would be needed to have any of these biological effects. And actually, I'm just curious because I didn't really, I couldn't get a good answer on this. They had this lovely little dotted line on their figures of what they considered to be unacceptable concentrations in serum in the nanomolar range. And any thoughts of where that came from, that like magical line, well, if you're above this, it's clearly bad news, which I think you and I both agree that's not necessarily true. Indeed, and that value is 0.5 nanograms per mill. And that value came from something called the ICH. I don't know how familiar you are with the agency participates in associations where they come and they talk about methodologies and they try to standardize it across different geographies. And so the ICH is very important in terms of that standardization. And so if you have a manufacturing process where you have an unidentified chemical from a manufacturing process and you go, well, I don't know anything about this chemical, could it be harmful? And the 0.5 nanograms per mill came about from this impurity evaluation where you have one in 100,000 risk of cancer. And if you're below 0.5 nanograms per mill, that qualifies as being unlikely. Now what's not known by most people is that this incorporates genotoxic impurities. In other words, I talked about DNA reactivity. And by the way, the UV filters don't have that DNA reactivity. So assigning a threshold of 0.5 to non-genotoxic materials is in my estimation and others as well a serious mistake because they aren't genotoxic. So that 0.5 nanograms per mill, the dotted line that's on the figures, is, you know, for we don't know anything about this material. That's how that came about. Yeah. No, that I appreciate that explanation because I couldn't make heads or tails as how they created this arbitrary line. So I think this paper, your work, has really opened the door to hopefully moving things forward in terms of how hopefully sunscreen safety is evaluated. Do you foresee any possible scenario where maybe the MOA approach is adopted as opposed to the historic approach for evaluating safety? Is that even on the table? I would like to think so, Adam. I truly believe that, you know, that the individuals in the agency, they're smart people. They're dedicated. They're really concerned about the health of citizens in the U.S. who are exposed to OTC drugs, to prescription drugs. And they take their responsibility very seriously. I hope that they, and what we had asked them and they would not entertain this request, which was, we want to work with you. We really want these UV filters back in good standing because they're so important. They're so important for patients. They're so important for consumers. The protection is one of the few things where you can really point to and say this has a health benefit in a protective fashion. There aren't very many things that exist like that. And so I'm optimistic. I remain optimistic. I will be forever optimistic. They'll look at this, they'll consider the brains behind this and they will say maybe there's something here that we can utilize, not only for OTC, UV filters, but perhaps for other materials that have extensive human exposure. Now if you're asking me if this was a new chemical entity, look, if I didn't have any data at all, I would say, well, I would just assume see some data in some sort of mammalian species before I went into humans. But my goodness, these have been used for 40 to 50 years. Wouldn't you have expected some adverse event to materialize in that period, even if it wasn't used by the way in the must studies, you know this atom, 2 milligrams per centimeter squared, 75% of the body surface area applied every two hours. I encourage you to try that at home. I'm going to pass on that recommendation, but I appreciate the offer. Well, I think everyone just heard it here. What I'm gathering is there's an open dinner invitation for the FDA. We hope they RSVP, yes, to kind of sit down and have these discussions to maybe bring us into the modern era of how we look at it. It's a really good point. For something that's completely unknown, not having decades of animal and human experiential data. I think that's where maybe some of the Safe Suns Green Act or proposal of utilizing not the rigid clinical trial, like following validay research tools that aren't practically or not practical whatsoever, clinically relevant, rather using experiential data and population data that's out there that maybe we can come to some conclusion here, both about what we've had this far, but maybe even getting some new filters into the mix. Now, bring it down to the clinical level in wrapping up, how do you feel dermatologist share interpret these findings and relaying them to maybe there or incorporating them into how they counsel patients worried about sunscreen safety, seeing a video from their favorite influencer. There are too many to count saying, don't apply sunscreen, they cause cancer. Of course, that person's the expert, how do you take all this great work and relay it in a digestible way for the patient if you were the dermatologist? Wow. What an excellent question. If I were. If I were a dermatologist and I was counseling a patient, I would say, look, there is extensive evidence that use, topical use of sunscreen products with these organic filters, do not, do not impact cancer other than preventing. I like that. Answer from a known human carcinogen, which is solar UV. And I would encourage patients to use daily facial products because the face is always exposed to UV. Recreational products, look, if you're going to be out in the sun and most people use one and a half hours as sort of a threshold, you should be using a sunscreen to really reduce the dose of solar UV. And at the same time, understand that these are not perfect. They're not perfect, which allows for any beneficial effects of solar exposure to radiation, to have their positive benefits of vitamin D, for example. And we really want people to experience the outdoors. I mean, that's sort of the beauty, I think, behind photo protection. Is you can without the acute and I think in many instances, the chronic skin damage that can occur with solar UV exposure. Yeah, I think to your point, you can have your cake and eat a tooth, thanks to sunscreens. That was so well said. Jay, it has been such a pleasure speaking with you. In my eyes, you are a dermatology superhero doing this type of work because we are fighting an uphill battle, combating misinformation. And it's misinformation that is harmful. It is misinformation that while certainly might increase some of our volumes in shopping out cancers and addressing accelerated photo aging, at the end of the day, we were all on the same side, which is the side of the patient and preventing health issues. And I hope this work gets out where it needs to be. I hope we see change at every level, both in the clinic, in the educational sphere, with respect to what patients digest and consumers digest, but also at the highest level of regulatory bodies to ensure that accurate information and realistic and pragmatic approach is to assessing safety and efficacy really translate into an armament that allows us to probably combat a known carcinogen. So thank you so much for joining me today. Oh, you're most welcome, Adam. And I hope the next time we get a chance to talk about nanotechnology. I have been being interested in that and I know you do too. But I guess the last thing I'd like to finish with is the following. You know, the agency has asked for a number of animal testing and we really think that that's had its day. And in many parts of the world, you can't do animal testing or you cannot sell the product if you've tested it in animals. And so we're continuing to push on new methodologies, often abbreviated names. So that's a new approach methods to better assess the safety of consumer products, also of prescription products. I believe that we're getting there. So it's been a pleasure. Thank you for the invitation. Again, a real honor to have this opportunity to speak with you. Now, thank you. And I'm going to say it again. Super hero. Thank you for all you do and thanks to all of you for joining us for this special edition of the JDD Podcast. You've been listening to JDD Podcast, Ask the Investigator, the number one podcast for dermatology pearls. Our host is Dr. Adam Friedman. The podcast is produced and edited by Emily Lynch-Frees. Our theme music is designed for life by young presidents. New episodes are available the first Friday of every month. Check us out at JDDOnline.com/podcast or wherever you listen to podcasts. And if you want to talk to us about this or any other episode, email us at
[email protected]. Subscribe and review the podcast on iTunes or Google Play and don't forget to catch our next episode. Thanks for listening.
PodcastTranscript AI