Controlling Systemic Inflammation by Careful Formulation of Topical Skin Care Products: Our Bodies Didn’t Evolve With All the Current Chemicals in Skin Care Products

Although man is still rapidly evolving, he has not co-evolved with all of the modern chemicals made by man, including those in cosmetic products. Care must be taken when formulating products so that commonly used ingredients, such as polyethylene glycol, can be substituted with safer ingredients to which man has adapted and that will not cause irritation and inflammation. This is especially important given that induction of skin inflammation will cause systemic inflammation. A review of the literature and of commercially available products was made to highlight techniques and products that remediate inflammation or induce inflammation. Many skin care products contain chemicals that induce irritation and inflammation that may lead to chronic, systemic inflammation. Well studied natural products, especially skin identical chemicals, may offer an advantage compared to recent man-made chemicals in cosmetic and topical formulations and help to reduce skin inflammation as well as skin derived systemic chronic inflammation.

not the grandchild was exposed to atrazine, a commonly used herbicide (McBirney et al, 2017). Barrier disruption (Fluhr et al, 2005) and atopic dermatitis (AD) may result from many of these exposures to the skin (Kim, 2015; Kantor and Silverberg, 2017). Simple barrier disruption, such as through tape stripping, leads to the release of inflammatory cytokines, an up to five-fold increase in the expression of MHC class II antigens, activated Langerhans cells, a type of macrophage-dendritic cell hybrid (Doebel et al, 2017) and induced T cell proliferation (Katoh et al, 1997). In turn, inflammatory cytokines, but probably not inflammatory T cells (Shams et al, 2017), in the skin can  [13][14] in England (Shamssain, 2007) is likely to represent a true change in prevalence and environmental factors are likely causative (Deckers et al, 2012). Our exposome likely accounts for 70-90% of chronic diseases (Smith and Rappaport, 2010). In response to our exposures, the immune system is a learning system like the brain (Rook et al, 2017). In one aspect, having evolved to anticipate data input from our symbiotic microorganisms (microbiota), and ingested and topical chemical exposures that are particularly abundant in the gut and skin, and from organisms and chemicals in the natural environment, modern lifestyles have decreased and distorted these inputs. This distortion of symbiotic inputs, including those from non-commensal bacteria and man-made chemicals, contributes to failing regulation of the immune system. Failing immunoregulation contributes to increases in chronic inflammatory disorders, such as allergies, autoimmune disease and inflammatory bowel disease, where the immune system is targeting things it should not attack. As humans co-evolved with microbial communities and chemicals (those eaten in plants for example), many microbial products and chemicals were co-opted to play roles as signals for the development and function of essentially all organ systems, 4 including the brain (Dalile et al, 2019). It was not possible to build a sufficient repertoire of receptors to recognize a vast and rapidly changing array of microbial molecules by simply duplicating receptor genes and evolving variants. This would have added enormously to the size of the genome and yield a response that is too slow. Such a mechanism could never keep up with microbial evolution and the manufacture of new chemicals. Therefore the "adaptive" immune response appeared. Invertebrates, with their simpler microbiotas, do not have this type of adaptive immune system. Part of the mechanism depends on exposure to as many microorganisms and natural chemicals as possible. Thus the adaptive immune system develops a repertoire that is relevant to the microbial and chemical environment in which the individual lives, rather than to a microbial and chemical environment from the distant past, but to develop this repertoire it must have an "educational" input of microorganisms and chemicals from the gut and the environment. The first influenza virus infection during the first three years of childhood, termed immune imprinting, is recognized for its influence on subsequent infections and vaccinations (Kelvin and Zambon, 2019). The early imprinting event initiates a cascade of innate and adaptive immune responses, including from T cells (Nelson and Sant, 2019), leading to an immunological memory retained over a person's lifetime. The adaptive immune system generates a vast repertoire of receptors (antibodies for example) by mutation, so few genes are required. Thus a new repertoire is generated de novo in each individual. Then lymphocytes bearing relevant receptors are selected and clonally expanded, while useless ones, or any that recognize the individual's own tissues, are eliminated.
Given that most of our diseases result from our exposome (Rapapport, 2016), the argument is put forth that physicians need better education in epidemiology, an interrogative epidemiological database, and better diagnostic tools for discovering a inflammatory responses. These inflammatory responses induced by dioxin can be exacerbated by co-treatment with retinoic acid leading to increased skin lesions (Rudyak et al, 2018). Retinoic acid is commonly used for a number of skin conditions, including acne. Part of the exposome, along with exposure to foreign chemicals in the environment, are our own stress induced chemicals such as cortisol and prolactin.
Stress, acting through increased cortisol production can impede protein synthesis and wound healing (Christian et al, 2006). Likewise, stress can cause increased levels of prolactin (Lennartsson and Jonsdottir, 2011). Recently discovered in keratinocytes is that prolactin enhances their proliferation (Girolomoni et al, 1993), and interferongamma-induced production of (C-X-C motif) ligand 9 (CXCL9), CXCL10, and CXCL11. Therefore prolactin may promote plaque formation and Th1 cell infiltration into stressed skin through the actions of these chemokines (Kanda and Watanabe, 2007). While the focus of this paper is on chemical exposure to the skin, psychological stress may help to trigger or exacerbate the effects of the chemicals (Vesterinen et al, 2017). For example, mast cells in the skin are activated by stress that produce stress hormones and inflammatory factors. This activation may lead to a vicious cycle of stress-induced inflammatory events associated with acne, atopic dermatitis, psoriasis and pruritus (Arck et al, 2006 (Auriemma et al, 2013), and indeed, fiber can reduce the symptoms of AD (Gruber et al, 2015). A heredity component, including possible genetics, has also been associated with AD.
Considering genetics, with a population explosion where man has expanded by at least three orders of magnitude over the past 400 generations (Keinan and Clark, 2012), selection is dwarfed by the effect of genetic drift in human populations (Eaaswarkhanth et al, 2016). With this drift and lack of selection, human diseases may negatively affect fitness but fail to be eliminated from the population. There are thousands of relatively common disease-susceptibility variants in modern human populations. A small portion of common genetic variants yield relatively large phenotypic effects that remain in the human population, as exemplified by the FLG LoF variants of fallagrin. FLG is one of the primary loci that has been associated with atopic dermatitis (AD). The fitness advantage of not being susceptible to the FLG LoF mediated disease appears not to be high such that even extant, wild chimpanzees carry the LoF variant too (Eaaswarkhanth et al, 2016). Reduced fillagrin function will lead to disorganization of the stratum corneum and resultant trans epithelial water loss (TEWL), and irritation and pruritus (Gruber et al, 2011). With the explosion of population growth also comes an increasing exposure of human beings to novel pathogens, particularly the crowd infections that were not part of our evolutionary history (Rook et al, 2017). in an increased probability of comorbidity from IBD and RA.
As humans coevolved with plants and ate a diet rich in vitamin C we lost our ability to make vitamin C. Compared to other genes, the GLO gene for making vitamin C was susceptible to being lost because the gene makes a single compound, and is unnecessary for the synthesis of other molecules (Linster et al, 2007). Only the loss of vitamin C is incurred with the loss of this gene. Therefore, with a high intake of plants and their vitamin C, primates no longer needed to make vitamin C and eventually lost 7 the genetics to make that one molecule, and only that one molecule. Normal skin contains high concentrations of vitamin C similar to other tissues, and because it is dietarily derived, vitamin C is transported into cells from the blood vessels present in the dermal layer (Pullar et al, 2017). More vitamin C is found in the epidermal layer than in the dermis, with differences of 2-5-fold between the two layers reported (Rhie et al, 2001). Vitamin C levels are lower in aged or photodamaged skin. Excessive exposure to oxidant stress by pollutants or UV irradiation is associated with depleted vitamin C levels in the epidermal layer (Shindo et al, 1994) Important to the skin barrier, vitamin C enhances the late differentiation of keratinocytes, overcomes the oxidative stress induced by differentiation, and maintains the integrity of the stratum corneum (Ponec et al., 1997;Savini et al., 2002). One study of vitamin C in atopic dermatitis demonstrated a reduction in serum levels of vitamin C that correlated with the severity of AD (Shin et al, 2016). No such correlation was found for vitamin C levels in the epidermis. Unfortunately the study made no comparison of vitamin C levels in the epidermis on control subjects, and so evidence as to whether the vitamin C levels in the epidermis of AD patients are normal or not was not presented. The benefits of topical vitamin C application are numerous. For example, a 10% ascorbic acid (water soluble) and 7% tetrahexyldecyl ascorbate (lipid soluble) formula was shown to decrease wrinkles and increase collagen production in a clinical trial (Fitzpatrick and Rosten, 2002). In clinical studies, vitamin C-containing topically applied solutions have been shown to reduce UV-induced thymine mutations, thereby potentially reducing the risk of photocarcinogenesis (Murray et al, 2008). A number of other benefits have also been observed for topically applied vitamin C (Al-Niami and Chiang, 2017). Thus, the topical application of a coevolved molecules, vitamin C, is beneficial to the skin.
A recent NY Times article (Sanders, 2019) written by a physician details the life threatening episodes one man had in severe reaction to a common chemical, PEG, found in pharmaceutical products, skin care products, personal lubricants, and as a food additive, that resulted in anaphylaxis. Without an epipen and subsequent emergency room visit, the patient would have died. Topical application of PEG led to an immediate skin reaction in this patient. The episodes he experienced with one chemical represent 8 the broader problem of modern man's exposure to thousands of manmade chemicals to which our bodies have only recently been exposed in evolutionary time, and therefore potentially harmful chemicals to which we have not evolutionarily adapted, and that may be leading to diseases such as cancer (David and Zimmerman, 2010). Importantly, new research shows that inflammation in the skin will translate to blood borne systemic studied thirty-three older adults between the ages of 58 and 95 who applied a lipidbased emollient cream over their entire bodies twice a day. At one month into the study, the blood levels of three cytokines, interleukin-1 beta, interleukin-6, and tumor necrosis factor (TNF) alpha, were measured. These factors have been implicated in age-related inflammatory diseases and mortality (Lee et al, 2012). Using the cream reduced the amount of the three cytokines compared to the participants' levels before using the cream, and also reduce the levels of the cytokines of similarly aged adults who did not use the cream. The cream was so effective that the regimen lowered participants' inflammatory cytokine levels to that of people in their 30s, suggesting that epidermal repair can reverse systemic inflammation. This study suggests that formulation of a topical skin care product can not only control inflammation in the skin, but also systemically and therefore care is required in the choice of topical products and their ingredients to be administered to patients.

Methods
The ingredients of a number of skin care products were examined for their potential irritating and inflammatory effects, or ingredients that may lead to positive, antiinflammatory effects in the skin.

Examples of Potentially Therapeutic Chemicals in Skin Care Products
The stratum corneum is the principle UV filter in Caucasian skin (Kaidbey et al, 1979), and the barrier to water loss and penetration of irritants into the skin (Kezin and Jakasa, 2016  inhibits the movement of water and electrolytes (Ghadially et al, 1992). The nonphysiological petrolatum lipids can very rapidly, but only partially restore barrier function (Elias, 2006). Another disadvantage of non-physiological lipids is that they also can inhibit the normal permeability barrier repair mechanisms and thus not repair the underlying abnormality in lamellar structure (Elias, 2006).

Example of Misinformation in Skin Care Marketing
Some confusion seems to exist among practicing physicians about the best formulations for restoration of the barrier function using exogenous lipids. . However, if one reads the study, the MLE formula was compared to a formula that contains a very different set of ingredients (see Table 1  Using this molecule that we coevolved with, Schwarz et al (2017) showed that topical butyrate can modulate Treg function such that hapten induced skin inflammation was significantly reduced. One product on the market that contains the three necessary lipids, urea, and butyrate is Barrier Renewal Cream by NeoGenesis Inc.

Discussion
The exposome accounts for about 70-90% of our chronic diseases (Smith and Rappaport, 2010;Rappaport, 2016). The exposome includes many new and untested chemicals that, along with rapid genetic drift and lack of selection, and the modern environment that precludes functional training of the adaptive immune system, has led to a rise in many health conditions, including atopic dermatitis. In particular, topical skin care products often contain ingredients that were unknown to humans as we evolved, such as PEG and polysorbate. Skin care products may also contain natural ingredients at concentrations that we didn't evolve with, or natural ingredients that did not evolve to be in contact with our skin. This includes ingredients that are biologically derived, such as the "Induced Pluripotent Stem Cell Extract" derived from genetically modified human cells in an extraction process, yielding a potentially dangerous cancer causing and prion-like set of molecules. This also includes the biomolecules derived from BMSCs that are normally only present in the skin during brief episodes of significant wounding.
If applied to the skin frequently, the BMSCs derived molecules will induce inflammation, proliferation, and resident stem cell exhaustion . High levels of natural oils if not formulated into a proper mix of the necessary lipid types to maintain barrier function can induce inflammation. As such, many of these new chemicals, or the use of chemicals in an unnatural manner, most of which have not been thoroughly tested, may have negative side effects in man. Therefore, the argument is advanced that natural products, those that have evolved with man and are used in a manner in which they evolved, including proper use during man's developmental stages (recall the aforementioned problems with linoleic acid in neonates but not adults) and have been thoroughly studied, may best serve skin health and consequently systemic health.
Moreover, given that we evolved an adaptive immune system that requires training early in life, the modern world with its limited number of natural organisms and its altered sets of chemicals, leads to exposure to chemicals with which we have not adapted. Thus natural products that are not skin identical, and to which we have not adapted, may induce an allergic reaction. As example, skin identical ingredients that serve as   Phys. 146, 215103.