Sensitization and Phototoxicity

Sensitization involves allergic reactions of the immune system. Sensitization is a three-step process with an initial exposure followed by an induction period that involves the development of antibodies or lymphocytes in response to an antigen. The induction period usually does not produce symptoms. The third step is called the challenge or elicitation reaction, which occurs on subsequent treatments or exposures. Clinically, elicitation occurs about 2 weeks (10 days to 3 weeks) after induction. At this stage, an inflammatory response usually occurs, but if the walling off process is not effective, more severe symptoms result. 

The mechanism of psoralen phototoxicity has been studied extensively, and 5-methoxy psoralen, which is only 0.33% of Bergamot oil, is believed to be the principal phototoxic component of the oil [190]. 5-Methoxy psoralen absorbs ultraviolet light above 310 millimicrons and is elevated to an excited state (free radical). The psoralen radicals link to pyrimidine bases 

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Coumarins Many coumarins are skin sensitizing and phototoxic and, consequently, they should be used with caution. Properties associated with coumarins are ... 

The Federal Flazardous Substances Acts (FHSA) of 1940 and of 1960 define five areas of acute toxicity/irritation that are of primary importance for the development and sale of consumer products acute oral toxicity, dermal toxicity, primary dermal irritation, eye irritation, and acute inhalation toxicity. The FHSA act describes recommended test conditions in detail for these toxicity/irritation phenomena. Some knowledge of the potential for sensitization and phototoxicity are also relevant, and to provide longterm safety assurance, potential carcinogenicity and mutagenicity must also be considered. 

Research Institute for Fragrance Materials (RIFM) testing is generally limited to acute oral and dermal toxicity, irritation and dermal sensitization, and phototoxicity of individual materials, and there is little effort to address synergistic and modifying effects of materials in combination (Johansen et al., 1998). 

Additional considerations for inhalation/intranasal route acute inhalation, application site, and pulmonary sensitization studies for parenteral route acute parenteral toxicity and application site studies mucosal use application site evaluation transdeimal and topical drugs application site and phototoxicity/photoallergy evaluation. Photocarci-nogenicity is a conditional option for transdeimal and topical excipients. 

As part of the safety assessment the assessor must consider the chemical structure and all the available information regarding the toxicological profile of the material. The decision to proceed with human testing should only be made if the information available provides sufficient confidence that the volunteer will not be exposed to undue risk. Key toxicological endpoints of concern for moisturizing products include skin corrosivity, percutaneous absorption, genotoxicity, skin sensitization, skin irritation, systemic toxicity, reproductive toxicity, and phototoxicity. 

The essential oil is a pale yellow with a light, bitter-sweet floral odour. The absolute is darker and more viscous with an odour closer to the original flower. The main chemical components of the essential oil are the alcohol lin-alool (30-37%), the ester linalyl acetate (6-17%) and monoterpenes limonene (12-18%) and [3-pinene (12-15%). Also present geraniol (2-3%), nerol (1-3%), nerolidol (3-6%), citral and jasmone. Both the plant and the essential oil have many established uses. The essential oil is considered to be one of the most effective as a sedative, carmative and antidepressant and often used to treat insomnia. It is also claimed to be relaxant for smooth muscle (internal, involuntary muscles) especially those of the gut. Suitable for all skin types, both the essential oil and hydrolat are versatile materials for the aromatherapist. Considered safe as it is nonirritant and non-sensitizing and an example of a non-phototoxic citrus essential oil. 

The equation above defines a phototherapeutic index and was applied to in vitro studies for which all the parameters are available. Table VI presents a few relevant examples. The comparison between Photofrin and Foscan is straightforward because the same cell line was employed and reveals that the Foscan is a more efficient sensitizer. The comparison between the other sensitizers involves different cell lines and must be made with caution. However, sul-fophenylbacteriochlorins with chlorine atoms in the ort/io-positions of the four phenyl rings have shown similar dark cytotoxicities and phototoxicities toward various cell lines (89,100,105) and seem to be promising sensitizers for oncologic PDT. 

Several sensitive and convenient models can be used to test for phototoxicity.f " Guinea pigs, rabbits, and mice are the most commonly used species. Normal, albino guinea pigs and rabbits must be shaved or their... 

A. millefolium contains sesquiterpene lactones, polyacetylenes, coumarins, and flavonoids. Extracts have often been used in cosmetics in concentrations of 0.5-10%. A. millefolium was weakly genotoxic in Drosophila mela-nogaster. In provocative testing, patients reacted to a mix of Compositae that contained yarrow, as well as to yarrow itself. In clinical use, a formulation containing a 0.1% extract was not a sensitizer and alcoholic extracts of the dried leaves and stalks of the flower were not phototoxic (6). However, positive patch tests to A. millefolium have been reported (7). 

Parahens are nonmutagenic, nonteratogenic, and noncarci-nogenic. Sensitization to the parahens is rare, and these compounds do not exhibit significant levels of photocontact sensitization or phototoxicity. 

Pharmacokinetic aspects must be taken into account in cases in which the in vitro screening indicates that the compound is likely to cause phototoxic reactions in vivo. This includes information about in vivo metabolites and degradation products (if available). Phototoxicity is generally dose dependent, i.e., dependent on the concentration of the drug sensitizer and the intensity of the incident radiation at the site of action. Prior to a phototoxic reaction, the sensitizer must be distributed to tissues that are exposed to irradiation and further absorb the light that penetrates these tissues. If no pharmacokinetic data are available, the probability of being retained in a lipophilic medium can be predicted to some extent from the pKa and/or the log P value of the compound. 

Dermal exposure to toxicants can produce a variety of effects, such as primary irritation, sensitization reactions, phototoxic skin reactions, photoallergy, urticarial reactions, hair loss, chloracne, and cutaneous cancer. These toxic effects and the nature of the reactions are discussed in this section. 

Iodine solution in its earlier form without povidone (tincture of iodine) proved suboptimum for chronic treatment of open wounds because of staining of the skin, local irritation, and sensitization of skin. Experimentally, such problems are avoided with PVP-I as solubility increases and chemical reactivity decreases due to binding with povidone, A review of the safety literature evaluating PVP-I concludes there is a lack of irritation as demonstrated by skin patch tests, sensitization assays, phototoxicity and allergenicity assays in humans, and eye and dermal Draize irritation assays in rabbits [17],... 

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