OPINION


Although these studies were performed using purified Bacillus bacterial protease enzymes, occupational respiratory sensitisation has also been reported in medical laboratory workers handling bromelain during their day-to-day work.4 Indeed, Baur and Fruhman5


had earlier


reported a confirmed case of occupationally-derived sensitisation to bromelain in a pharmaceutical worker handling purified enzyme over a 10-year period. In this specific case, asthma and rhinitis were also reported by the affected worker concurrently with handling of bromelain at work. In investigating the case, respiratory symptoms were recorded during both respiratory and dietary challenge with unpurified pineapple material.


Therefore, although classic toxicological principles and techniques (as described in the SCCS Notes for Guidance) are suggestive of protease enzymes being acceptable as cosmetic ingredients, practical human clinical data reveal the opposite. Consequently, cosmetic safety assessors would be lulled in to a false sense of security if, for example, they only utilised techniques such as read-across to other exposure scenarios such as dietary intake following usage of the enzymes as tenderisers. For protease enzymes, the only definitive way to demonstrate their safety as cosmetic ingredients would be to undertake extensive clinical testing, including invasive blood sampling, which could be considered outside of the scope of the SCCS Notes for Guidance.


Epidermal growth factor Turning now to the proliferation of skin care products containing peptides depicted as epidermal growth factor (EGF), and described by Hart-Davis in January 2011 as being ‘the next big thing’,6


ingredients


which at the very least should be used with caution in the light of their biological action. EGF is one of a family of growth factors, being a polypeptide of 53 amino acids, which possesses the ability to stimulate the growth and differentiation of epithelial tissues, fibroblasts and endothelial cells. This effect is achieved through the molecule binding to specific cell surface EGF receptors, to stimulate mitogenic responses in the target tissue.7


Other


effects noted for EGF include stimulation of cell migration and development of new blood vessels within the tissue undergoing repair.


Of interest to the cosmetologist is the knowledge that EGF plays a major role in tissue repair and wound healing, in concert with a number of other naturally- occurring growth factors and cytokines. This observation led ultimately to the


82 PERSONAL CARE April 2012


EGF stimulates cell migration and development of new blood vessels within repairing tissue.


development and usage of EGF as a therapeutic agent in the management of wounds and burns, for both internal and external tissue repair. But, and importantly from the cosmetic product safety assessment point of view, these cellular events are also common critical processes in the development of cancerous tumours, which led to concerns about the predisposition of patients being treated with EGF to cancer development. However, the experimental evidence suggests that EGF does not ‘initiate’ tumours, which means it does not transform normal cells in to cancerous cells. Rather, EGF is a ‘promoter’, which means that it will stimulate the growth of cells that have already been transformed in to potential tumour cells.


In this context, Berlanga-Acosta J et al.7 reported that the cancer incidence among patients being treated with EGF for the management of burns essentially matched an untreated control group. However, in marked contrast, following a review of data for patients being treated with a recombinant human platelet-derived growth factor for the treatment of diabetic ulcers, USA FDA warned that there was an increased risk of death due to secondary cancerous tumours among patients being treated with the preparation; the types of cancer recorded were varied and remote from the site of treatment with EGF. Consequently, it is now stated in an ‘Important Drug Warning’ issued by the manufacturer of the preparation that this EGF should be used with caution in patients with known malignancy, and that the material should only be used when the benefits can be expected to outweigh the risks.8


Although EGF would be expected not to


penetrate the skin into the blood due to its molecular size, clinical studies clearly demonstrate changes in skin structure and morphology in both the epidermis and upper dermis at the site of application.9 Mehta and Fitzpatrick10


state that evidence


suggests a double feedback loop exists in the skin whereby keratinocytes stimulate fibroblasts to synthesise growth factors that in turn stimulate keratinocyte proliferation, which in essence acts as an amplification of the initial effects of topically-applied growth factors. With respect to the classic toxicological end-points as described in the SCCS Notes for Guidance, Marachin et al.11


reported the


outcome of a toxicology testing programme in various animal models with human urinary EGF. This testing revealed that while urinary human EGF was devoid of mutagenic or teratogenic activity, there were pronounced pharmacological effects which produced severe impairment of the main organ systems, leading to the death of some animals. However, the SCCS Notes for Guidance essentially do not take account of the reputed biological action of cosmetic ingredients. Therefore, the cosmetic toxicologist may not fully appreciate the potential hazard of novel ingredients if the biological action of the cosmetic ingredient under review is not considered during the safety assessment process.


Nevertheless, there is also a question mark concerning the regulatory status of the some EGF peptides used as cosmetic ingredients.


In North America, the growth factors and cytokines commonly used as cosmetic ingredients are generally produced from cultured human dermal fibroblasts,12,13 making them specifically human-derived. These growth factors would be considered illegal as cosmetic ingredients in the EU, according to EU Directive 76/768 EEC, Annex II, No. 416. This entry specifically prohibits the use of cells, tissues or products of human origin, including RH-oligopeptide-1, which is described as a recombinant human peptide produced by microbial fermentation, where the starting gene has been directly isolated from a human cell. Other biosynthetic routes for EGF production include extraction from cell culture growth media or plant tissue genetically modified to produce human-like growth factors, where a human-identical recombinant gene has been transfected by a vector organism in to a host plant. Therefore, when considering the usage of peptide growth factors such as EGF as cosmetic ingredients, not only should the cosmetic toxicologist consider the regulatory position of such peptides, it is also crucial that a holistic approach is adopted to the safety assessment of the


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