Benzene absorption in animals and man: an overview.

Benzene is a widespread, naturally occurring substance of environmental concern as systemic exposure in humans is proven to be carcinogenic. Dermal exposure is a common and significant route of systemic entry and percutaneous absorption is critical in exposure risk assessment. This article reviews the scientific principles, methodologies, and research behind the multiple steps of the percutaneous absorption of benzene in animals and man and the application of this information to optimize exposure risk assessments. A focus on occupational exposures to benzene is made with an exploration of the limitations of current preventative measures and hazard assessments. Finally, recommendations for future research to fill existing knowledge gaps are made.

Human skin penetration of a copper tripeptide in vitro as a function of skin layer.

OBJECTIVE AND DESIGN: Skin retention and penetration by copper applied as glycyl-L-histidyl-L-lysine cuprate diacetate was evaluated in vitro in order to assess its potential for its transdermal delivery as an anti-inflammatory agent. MATERIALS AND METHODS: Flow-through diffusion cells with 1 cm(2) exposure area were used under infinite dose conditions. 0.68% aq. copper tripeptide as permeant was applied on isolated stratum corneum, heat-separated epidermis and dermatomed skin and receptor fluid collected over 48 h in 4 h intervals using inductively coupled plasma mass spectrometry to analyze for copper in tissues and receptor fluid. RESULTS: The permeability coefficient of the compound through dermatomed skin was 2.43 ± 0.51 × 10(-4) cm/h; 136.2 ± 17.5 µg/cm(2) copper permeated 1 cm(2) of that tissue over 48 h, while 97 ± 6.6 µg/cm(2) were retained as depot. CONCLUSIONS: Copper as tripeptide was delivered in potentially therapeutically effective amounts for inflammatory disease.

Human skin retention and penetration of a copper tripeptide in vitro as function of skin layer towards anti-inflammatory therapy.

OBJECTIVE AND DESIGN: The skin retention and penetration characteristics of copper applied as glycyl-L-histidyl-L-lysine cuprate diacetate were evaluated in vitro in order to assess the potential for its transdermal delivery as anti-inflammatory agent. MATERIALS AND METHODS: Flow-through diffusion cells with 1 cm(2) exposure area were used under infinite dose conditions. 0.68% aq. Copper as a tripeptide was applied on isolated stratum corneum, on heat-separated epidermis and on dermatomed skin. Receptor fluid collected over 48 h in 4 h intervals was analyzed by inductively coupled plasma mass spectrometry for copper in tissues and receptor fluid. RESULTS: The permeability coefficient of the compound through dermatomed skin was 2.43 ± 0.51 × 10(-4) cm/h; 136.2 ± 17.5 µg/cm(2) copper permeated 1 cm(2) of that tissue over 48 h, while 82 ± 8.1 µg/cm(2) of copper were retained there as depot. CONCLUSIONS: Applied tansdermally as the tripeptide on human skin ex vivo, copper permeated the skin and was also retained in skin tissue in amounts potentially effective for the treatment of inflammatory diseases.

Fentanyl transdermal patches: overview of cutaneous adverse effects in humans.

Using Medline, Embase, and the Science Citation Index, we summarize the cutaneous adverse effects of transdermal and parenteral fentanyl. The fentanyl transdermal therapeutic system (TTS; patch) provides continuous systemic delivery of fentanyl (N-phenyl-N-(1-(2-phenylethyl)-4-piperidinyl) propanamide), a potent opioid analgesic, for 72 hours. Clinical studies of fentanyl TTSs demonstrated varying rates of irritation at the application site, ranging from none to 42%, with a median of 25%. Most descriptions of skin reactions included erythema at the application site, indicating irritant dermatitis. Skin testing in 2 subjects receiving parenteral doses concluded that although immunoglobulin E (IgE) antibodies to fentanyl exist, few cases of immediate-type allergic reactions to fentanyl have been substantiated. Comparing the reactions to anesthetic agents during allergenic testing demonstrated positive "wheal and flare" to fentanyl in only 1 of 50 patients (2%). Pruritus has been frequently reported during administration of epidural fentanyl, but allergenicity has not been shown. The few case reports of possible anaphylactic reactions to fentanyl have not clearly demonstrated fentanyl as the causal agent. In addition, transdermal and intravenous/epidural routes of administration may not be comparable because of large differences in plasma concentrations: When these results are taken together, fentanyl (TTS) has shown limited skin intolerance.

Is there evidence that methyl heptine carbonate causes allergic contact dermatitis?

The fragrance material methyl heptine carbonate has been cited as a moderately frequent cause of cosmetics-related allergic contact dermatitis. A review of the literature shows that when the underlying clinical data are analyzed, there is only one published case where a possible causal link to a cosmetic product has been established. Predictive tests in a computational model, in animal systems, and in volunteers have demonstrated a significant sensitization potential for this substance but reports of clinical cases of allergy are rare with no new reports appearing in the last two decades. The infrequence of reported cases of allergy may be linked to risk management procedures put in place by the International Fragrance Association (IFRA) more than 20 years ago.

Human stratum corneum penetration by copper: in vivo study after occlusive and semi-occlusive application of the metal as powder.

Aim of the study was to shed light on the long-standing controversy whether wearing copper bangles benefits patients suffering from inflammatory conditions such as arthritis. Sequential tape stripping was implemented on healthy volunteers to examine the diffusion of copper through human stratum corneum in vivo following application of the metal as powder on the volar forearm for periods of up to 72 h. Exposure sites were stripped 20 times and the strips analyzed for metal content by inductively coupled plasma-mass spectroscopy with a detection limit for copper of 0.5 ppb. Untreated skin was stripped in the same fashion, to determine baseline copper levels for comparison with exposure values resulting from exposure in respective volunteers. Under occlusion with exclusion of air, up to 72 h copper values decreased from the superficial to the deeper layers of the stratum corneum with gradients increasing commensurately with occlusion time, characteristic of passive diffusion processes. From the tenth strip on, however, levels reverted to background values. Under semi-occlusion allowing access of air by covering the skin with "breathable" tape, initial copper values lay significantly above baseline values and concentration gradients increased proportionally with occlusion time. At 72 h, from the tenth to the twentieth strip reaching the glistening epidermal layer, copper values continued at constant levels, significantly above baseline values. The results indicate that, in contact with skin, copper will oxidize and may penetrate the stratum corneum after forming an ion pair with skin exudates. The rate of reaction seems to depend on contact time and availability of oxygen. A marked inter-individual difference was observed in baseline values and amounts copper absorbed.

Sensitization to nickel: etiology, epidemiology, immune reactions, prevention, and therapy.

Nickel is a contact allergen causing Type I and Type IV hypersensitivity, mediated by reagins and allergen-specific T lymphocytes, expressing in a wide range of cutaneous eruptions following dermal or systemic exposure. As such, nickel is the most frequent cause of hypersensitivity, occupational as well as among the general population. In synoptic form, the many effects that nickel has on the organism are presented to provide a comprehensive picture of the aspects of that metal with many biologically noxious, but metallurgically indispensable characteristics. This paper reviews the epidemiology, the prognosis for occupational and non-occupational nickel allergic hypersensitivity, the types of exposure and resulting immune responses, the rate of diffusion through the skin, and immunotoxicity. Alternatives toward prevention and remediation, topical and systemic, for this pervasive and increasing form of morbidity are discussed. The merits and limitations of preventive measures in industry and private life are considered, as well as the effectiveness of topical and systemic therapy in treating nickel allergic hypersensitivity.

Skin penetration by metal compounds with special reference to copper.

The process of diffusion into and across the different structures of the skin by chemicals is reviewed, with particular attention given to copper compounds. The scarce data available from the literature indicate that, in contact with the skin, metallic copper will oxidize, and the compounds resulting will penetrate it. Results from our lab confirm that copper compounds formed with skin exudates penetrate the human stratum corneum in a time-dependent fashion. The only quantitative diffusion rates for copper compounds given in the literature so far refer to experiments performed on the cat in vitro and in vivo. Transformation of data from that study, based on certain assumptions, lead to estimated Kp values of 10(-6) to 10(-5) cm/h for the copper salts tested, values that lie at the lower end of skin diffusivity rates measured for transition metal salts. Permeability coefficients for aqueous copper sulfate and acetate through human epidermis in vitro measured in our laboratory are of the order of 10(-6) cm/h. For copper compounds formulated in combination with zinc compounds for therapeutic purposes, applied on dermatomed human skin in vitro in various vehicles, the apparent penetration coefficients Kp were in the range of 3.2 x 10(-6) and 1.6 x 10(-5) cm/h.

Thresholds of elicitation depend on induction conditions. Could low level exposure induce sub-clinical allergic states that are only elicited under the severe conditions of clinical diagnosis?

While numerous studies have examined dose/response relationships occurring in the experimental induction of contact allergic dermatitis, fewer have examined the effects of varying the doses of both induction and challenge. Recently published studies have however done this and they all show the same remarkable observation: the threshold of elicitation decreases as the doses used to induce the allergy increase. This has important implications. One is that it may be more complicated to determine clear threshold doses below which allergic responses are not seen. It is also proposed that normal exposure to weak allergens such as some fragrance materials may induce "sub-clinical" allergic states which will not be elicited under these same exposure conditions but which may become apparent under the more severe conditions of clinical diagnosis. This may explain why the prevalence of Patch test reactions to some fragrance materials is apparently increasing in the absence of any clearly documented "epidemic" of consumer complaints.

Copper hypersensitivity: dermatologic aspects.

Reports of immune reactions of both the immediate and delayed types due to cutaneous or systemic exposure to copper have been reviewed, in the endeavor to draw a comprehensive profile of the immunogenic potential of that metal and its compounds. The metal's immunotoxic potential is also briefly reviewed. In principle, as noted for other transition metals, the electropositive copper ion is potentially immunogenic due to its ability to diffuse through biological membranes to form complexes in contact with tissue protein. Based on predictive guinea pig test and the local lymph node assay (LLNA), copper has a low sensitization potential. Reports of immune reactions to copper include immunologic contact urticaria (ICU), allergic contact dermatitis (ACD), systemic allergic reactions (SAR) and contact stomatitis (STO), but considering the widespread use of copper IUDs and the importance of copper in coinage, items of personal adornment and industry, unambiguous reports of sensitization to the metal are extremely rare, and even fewer are the cases, which appear clinically relevant. Reports of immune reactions to copper mainly describe systemic exposure from intrauterine devices and prosthetic materials in dentistry, implicitly excluding induction of the hypersensitivity from contact with the skin as a risk factor. We provide a diagnostic algorithm that might clarify the frequency of copper hypersensitivity.

Skin irritation potential of copper compounds.

Data on the dermal irritation by copper and its compounds is scant, and its irritancy has not been determined, e.g., in terms of an irritant dose ID50. Irritancy of copper can only be comparatively characterized in relation to other metal salts. A rank order for the irritancy of metal compounds can be inferred from the patch test concentrations recommended as non-irritating for the purpose of cutaneous allergy testing: potassium dichromate 0.5% in petrolatum; copper sulfate, cobalt chloride and palladium chloride ex equo: 1% in aqueous solution, and nickel sulfate: 5% in petrolatum.

Copper hypersensitivity: dermatologic aspects--an overview.

Reports of immune hypersensitivity reactions of both the immediate and the delayed type following cutaneous or systemic exposure to copper are reviewed here in an endeavor to draw a comprehensive profile of the immunogenic potential of that metal and its compounds. The immunotoxic potential of the metal is also briefly reviewed. In principle, as noted for other transition metals, the electropositive copper ion is potentially immunogenic because of its ability to diffuse through biological membranes, forming complexes when in contact with tissue protein. Based on the results of the predictive guinea pig test and the local lymph node assay (LLNA), copper has a low sensitization potential. Reports of immune reactions to copper include immunologic contact urticaria (ICU), allergic contact dermatitis (ACD), systemic allergic reactions (SAR) and contact stomatitis (STO), but considering the widespread use of copper intrauterine devices (IUDs) and the importance of copper in coinage, items of personal adornment and industry, unambiguous reports of sensitization to the metal are extremely rare, and even fewer are the cases that appear clinically relevant. Most reports of immune reactions to copper describe systemic exposure as a cause--predominantly to intrauterine devices and to prosthetic materials in dentistry--implicitly excluding the induction of hypersensitivity from contact with the skin as a risk factor.

Nickel-induced hypersensitivity: etiology, immune reactions, prevention and therapy.

As a contact allergen causing type I and type IV hypersensitivity, mediated by reagins and allergen-specific T lymphocytes, expressed in a wide range of cutaneous eruptions following dermal or systemic exposure, nickel has acquired the distinction of being among the most frequent causes of hypersensitivity, occupationally as well as among the general population. In synoptic form the many effects that nickel has on the organism are presented, to provide a comprehensive picture of the aspects of that metal with many biologically noxious, but metallurgically indispensable characteristics. This paper reviews the epidemiology, the prognosis for occupational and non-occupational nickel allergic hypersensitivity (NAH), the many types of exposure and the resulting immune responses, immunotoxicity and rate of diffusion through the skin. Alternatives towards prevention and remediation, topical and systemic, for this pervasive and increasing form of morbidity resulting from multiple types of exposure are discussed. Merits and limitations of preventive measures in industry and private life are considered, as well as the effectiveness of topical and systemic therapy in treating NAH.