Evaluation of inhalation TTC values with the database RepDose

The thresholds of toxicological concern (TTCs) define limit values for substances of unknown toxicity below which dietary intake is considered to be of no concern to human health. The TTC concept has already been used for risk assessment of e.g. food contaminants or flavoring substances and is in discussion to be applied to other classes of compounds such as cosmetic ingredients, household products, non-relevant metabolites in drinking water, and impurities in pharmaceuticals. The present publication aimed to evaluate whether the current TTC concept can also be applied to define limit values for inhalation exposure, using a data set of 203 industrial chemicals from the database RepDose.     

Refining the threshold of toxicological concern (TTC) for risk prioritization of trace chemicals in food

Due to ever-improving analytical capabilities, very low levels of unexpected chemicals can now be detected in foods. Although these may be toxicologically insignificant, such incidents often garner significant attention. The threshold of toxicological concern (TTC) methodology provides a scientifically defensible, transparent approach for putting low-level exposures in the context of potential risk, as a tool to facilitate prioritization of responses, including potential mitigation. The TTC method supports the establishment of tiered, health-protective exposure limits for chemicals lacking a full toxicity database, based on evaluation of the known toxicity of chemicals which share similar structural characteristics. The approach supports the view that prudent actions towards public health protection are based on evaluation of safety as opposed to detection chemistry. This paper builds on the existing TTC literature and recommends refinements that address two key areas. The first describes the inclusion of genotoxicity data as a way to refine the TTC limit for chemicals that have structural alerts for genotoxicity. The second area addresses duration of exposure. Whereas the existing TTC exposure limits assume a lifetime of exposure, human exposure to unintended chemicals in food is often only for a limited time. Recommendations are made to refine the approach for less-than-lifetime exposures.     

The triggering role of allergic contact dermatitis in discoid lupus erythematosus

Abstract

Background: The onset and exacerbations of discoid lupus erythematosus (DLE) can be precipitated by several factors like needling, scratches, trauma, X-rays, heat, cold, pressure, tattooing, scars, allergic and irritant dermatitis and inflammatory dermatoses.

Objective: To investigate the role of allergic contact dermatitis (ACD) in devolopment and triggering of the lesions of DLE.

Materials and methods: This study was performed on 30 patients with DLE. European baseline series and cosmetic patch test series were used. At least 1+ reaction was accepted as meaningful.

Results: Twenty-three (76.7%) of 30 DLE patients and 16 (40%) of 40 control group patients were allergic to at least one allergen on standard patch test series. The difference between the groups were found statistically significant. Seventeen (56.7%) of 30 DLE patients and 6 (15%) of 40 control group patients were allergic to at least one allergen on cosmetic patch test series. The difference between the groups were statistically significant. The most sensitized allergens in both the groups were nickel sulphate, paraphenylen diamine, potassium dichromate from standard patch test series; quaternium 15, cocamidopropyl betain from cosmetic patch test series, in order.

Conclusion: This study is distinctive since it is the first study to determine the eliciting role of ACD on DLE by imposing standard and cosmetic patch test series on DLE and control group patients. Worldwide, there is no study based on this subject. In the DLE group, the results of sensitization on standard and cosmetic patch test series were higher and statistically significant. Larger studies are required to reveal the exact role.     

A case of generalized allergic contact dermatitis after laser tattoo removal

Tattoos are popular body decorations mainly done for cosmetic purposes. Regarded as a form of self-expression, tattoos reflect the character of the person wearing it. However, as tatoos are persistent visual markings on the body, frequently misperceived by the others causing tattooed to seek removal. Today most of the tattoos can be successfully treated with laser ablation. Here we present a case of generalized allergic contact dermatitis after laser tattoo removal which is a rare adverse reaction of laser tattoo removal.     

Application of the threshold of toxicological concern (TTC) to the safety evaluation of cosmetic ingredients

The threshold of toxicological concern (TTC) has been used for the safety assessment of packaging migrants and flavouring agents that occur in food. The approach compares the estimated oral intake with a TTC value derived from chronic oral toxicity data for structurally-related compounds. Application of the TTC approach to cosmetic ingredients and impurities requires consideration of whether route-dependent differences in first-pass metabolism could affect the applicability of TTC values derived from oral data to the topical route. The physicochemical characteristics of the chemical and the pattern of cosmetic use would affect the long-term average internal dose that is compared with the relevant TTC value. Analysis has shown that the oral TTC values are valid for topical exposures and that the relationship between the external topical dose and the internal dose can be taken into account by conservative default adjustment factors. The TTC approach relates to systemic effects, and use of the proposed procedure would not provide an assessment of any local effects at the site of application. Overall the TTC approach provides a useful additional tool for the safety evaluation of cosmetic ingredients and impurities of known chemical structure in the absence of chemical-specific toxicology data.     

Pharmacotherapy for allergic contact dermatitis

Allergic contact dermatitis is a highly prevalent, potentially chronic disease, with a significant economic and quality of life impact. Culprit causal allergen(s) can be identified though patch testing, the ‘gold-standard’ diagnostic method. For most people, identification and subsequent avoidance of their clinically relevant allergens will results in resolution of the dermatitis. However, when an avoidance regimen is not possible, or an allergen is not identified, patients potentially require symptomatic and immunosuppressive therapy to diminish the manifestations of their disease. This article reviews a therapeutic approach to allergic contact dermatitis.     

Allergic contact dermatitis from ophthalmics

In this article we summarize the recently described allergens responsible for allergic contact dermatitis due to ophthalmic drugs and contact lens solutions, and emphaage the need on how to perform diagnostic testing in this special clinical entity.     

Xanthone suppresses allergic contact dermatitis in vitro and in vivo

Xanthone is a phenolic compound found in a few higher plant families; it has a variety of biological activities, including antioxidant, anti-inflammatory, and anticancer properties. However, the molecular and cellular mechanisms underlying the activity of xanthone in allergic contact dermatitis (ACD) remain to be explored. Therefore, this study aimed to investigate the regulatory effects of xanthone in ACD in human keratinocytes (HaCaT cell), and human mast cell line (HMC-1 cell) in vitro and in an experimental murine model. The results demonstrated that treatment with xanthone reduced the production of pro-inflammatory cytokines and chemokines including interleukin (IL)-1β, IL-6, IL-8, and expression of chemokines thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in tumor necrosis factor (TNF)-α and interferon (IFN)-γ-stimulated HaCaT cells. Xanthone also suppressed the production of pro-inflammatory cytokines, chemokines, and allergic mediators in phorbol myristate acetate/A23187 calcium ionophore (PMACI)-stimulated HMC-1 cells. Xanthone significantly suppressed the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB) and activation of caspase-1 signaling pathway in vitro model. Additionally, xanthone administration alleviated 2,4-dinitrofluorobenzene (DNFB)-induced atopic dermatitis like-skin lesion by reducing the serum levels of immunoglobulin E (IgE), histamine, and pro-inflammatory cytokines and suppressing MAPKs phosphorylation. Xanthone administration also inhibited mortality due to compound 48/80-induced anaphylactic shock and suppressed the passive cutaneous anaphylaxis (PCA) reaction mediated by IgE. Collectively, these results suggest that xanthone has a potential for use in the treatment of allergic inflammatory diseases.     

Allergic contact dermatitis to para-phenylenediamine in a tattoo: a case report

It is highly popular among children and young adults to have temporary henna tattoos on their bodies in different colors and figures. Henna is a greenish natural powder obtained from the flowers and dry leaves of Lawsonia alba plant and its allergenicity is very low. Henna is also used in combination with other coloring substances such as para-phenylenediamine in order to darken the color and create a permanent tattoo effect. Para-phenylenediamine is a substance with high allergenicity potential and may cause serious allergic reactions. Here, we aimed to draw attention to the potential harms of para-phenylenediamine containing temporary tattoos by presenting a child patient who developed allergic contact dermatitis after having a scorpion-shaped temporary tattoo on his forearm.     

Acute stress modulates the irritant component of sensitizers in allergic contact dermatitis: implications for exposure assessment

Exposure of skin to noxious environmental stimuli can cause allergic contact dermatitis (ACD), which is a major health risk. Epidemiological studies have determined that 40% of workers report that their jobs are very, or extremely, stressful, and the number of chemicals to which workers are exposed increases each year. We hypothesized that combined exposure to a workplace stressor and a sensitizing chemical would alter the time course and magnitude of the skin immune response. We assessed the mixed exposure of chemical and restraint stress using three potent skin sensitizers, 2,4 dinitrofluorbenzene (DNFB), dicyclohexylcarbodiimide (DCC), and oxazolone, (OXA) on the ear swelling response in stress-susceptible BALB/c mice. Quantitative analyses showed that the dose-response relationship for each chemical followed a cubic trend. Although stress did not alter the shape of the curve, application of restraint stress on day 1 or on day 6 diminished the ear swelling response to 0.1% DNFB. However, if the concentration of the challenge dose was increased to a more irritating concentration, 0.25% DNFB, ear swelling was enhanced. Restraint stress applied on day 6 also increased ear swelling in response to the highly irritating sensitizer DCC, but not to the low-irritancy chemical OXA. These data support the hypothesis that dose-response relationships exist for sensitization with chemical and that restraint stress modulation of the ear swelling response is both chemical specific and dependent on the irritancy potential of the chemical.     

他克莫司软膏对小鼠变应性接触性皮炎的疗效观察

目的：评价他克莫司软膏治疗小鼠变应性接触性皮炎的疗效。方法：使用2,4-二硝基氯苯（DNCB）诱导小鼠背部变应性接触性皮炎,制造模型成功后,将60只小鼠随机分为正常对照组、模型组、卤米松组、糠酸莫米松组、丁酸氢化可的松、他克莫司组,每组10只,分别接受相应药物的治疗。观察各组小鼠皮损炎症程度、组织病理切片炎症细胞数量改变及皮损中IL-4和IFN-γ水平的变化。结果：他克莫司软膏能有效减轻小鼠背部皮损炎症程度,减少组织病理切片炎症细胞数量,调节皮损中IL-4和IFN-γ的水平;其疗效与卤米松相当,优于糠酸莫米松及丁酸氢化可的松。结论：他克莫司软膏对小鼠变应性接触性皮炎具有明显的治疗作用。     

Origin of the TTC values for compounds that are genotoxic and/or carcinogenic and an approach for their re-evaluation

The threshold of toxicological concern (TTC) approach is a resource-effective de minimis method for the safety assessment of chemicals, based on distributional analysis of the results of a large number of toxicological studies. It is being increasingly used to screen and prioritize substances with low exposure for which there is little or no toxicological information. The first step in the approach is the identification of substances that may be DNA-reactive mutagens, to which the lowest TTC value is applied. This TTC value was based on the analysis of the cancer potency database and involved a number of assumptions that no longer reflect the state-of-the-science and some of which were not as transparent as they could have been. Hence, review and updating of the database is proposed, using inclusion and exclusion criteria reflecting current knowledge. A strategy for the selection of appropriate substances for TTC determination, based on consideration of weight of evidence for genotoxicity and carcinogenicity is outlined. Identification of substances that are carcinogenic by a DNA-reactive mutagenic mode of action and those that clearly act by a non-genotoxic mode of action will enable the protectiveness to be determined of both the TTC for DNA-reactive mutagenicity and that applied by default to substances that may be carcinogenic but are unlikely to be DNA-reactive mutagens (i.e. for Cramer class I–III compounds). Critical to the application of the TTC approach to substances that are likely to be DNA-reactive mutagens is the reliability of the software tools used to identify such compounds. Current methods for this task are reviewed and recommendations made for their application.     

Application of the threshold of toxicological concern (TTC) concept to the safety assessment of chemically complex food matrices

The toxicological assessment of chemically complex food matrices (CCFM) usually is very time consuming, expensive and uses many animal studies. Improvements to obtain a more efficient assessment process remain limited as long as we retain traditional approaches to toxicological risk assessment. New concepts would be needed to achieve real innovations in risk assessment. The threshold of toxicological concern (TTC) potentially is such a concept that has existed for many years and recently has been further developed.The safety of CCFM is difficult to assess as there are numerous unknown substances present (often referred to as ‘Forest-of-Peaks’ in chromatographic analysis). Usually, for the evaluation of CCFM, a full safety assessment approach involving animal studies is needed, but the exposure to most substances is low and TTC might be applicable. However, to apply TTC efficiently to CCFM, a strategy is needed to deal with large numbers of unknowns (substances of which structural information is lacking). Therefore, we have drafted a framework for application of TTC in safety assessment of CCFM. This paper describes the criteria and development of the framework proposing a stepwise approach for the application of TTC in safety assessment of CCFM and future developments required.     

Exposure-triggered reproductive toxicity testing under the REACH legislation: a proposal to define significant/relevant exposure

Under the new REACH legislation, toxicological testing is required in relation to annual tonnages produced or imported. Requirements for toxicological information increase when production volume increases. The respective information requirements are laid down in the REACH Annexes VII-X. Concerning human toxicology, certain toxicological tests may be waived under specific conditions. Aside from waiving criteria such as technical feasibility, exposure plays a decisive role in the waiving process with the consequence that toxicological testing will not be required in case of "no relevant exposure", "limited exposure", "no exposure" or "no significant exposure" (as expressed in the documents). However, up to now criteria are lacking which precisely define these terms. Attempts have been made to establish cut-off criteria between "non-relevant" and "relevant" (detrimental) exposure based on external exposure concentrations and the threshold of toxicological concern (TTC) principle. In this paper we make a proposal and describe a strategy how to define the currently insufficiently described terms "relevant/significant" exposure. We propose to define relevant/significant exposure based on an endpoint-specific TTC approach, starting from a comparison of the tentative external exposure to the specific TTC. This can be followed by a refinement of exposure estimates and may culminate in the experimental determination of internal and target tissue exposure. This strategy enables a well-founded assessment of what "no relevant exposure" is and safeguards an appropriate level of protection of the general population. The feasibility of the approach is demonstrated for reproductive toxicity endpoints.     

Extension of the Dermal Sensitisation Threshold (DST) approach to incorporate chemicals classified as reactive

The evaluation of chemicals for their skin sensitising potential is an essential step in ensuring the safety of ingredients in consumer products. Similar to the Threshold of Toxicological Concern, the Dermal Sensitisation Threshold (DST) has been demonstrated to provide effective risk assessments for skin sensitisation in cases where human exposure is low. The DST was originally developed based on a Local Lymph Node Assay (LLNA) dataset and applied to chemicals that were not considered to be directly reactive to skin proteins, and unlikely to initiate the first mechanistic steps leading to the induction of sensitisation. Here we have extended the DST concept to protein reactive chemicals. A probabilistic assessment of the original DST dataset was conducted and a threshold of 64 μg/cm² was derived. In our accompanying publication, a set of structural chemistry based rules was developed to proactively identify highly reactive and potentially highly potent materials which should be excluded from the DST approach. The DST and rule set were benchmarked against a test set of chemicals with LLNA/human data. It is concluded that by combining the reactive DST with knowledge of chemistry a threshold can be established below which there is no appreciable risk of sensitisation for protein-reactive chemicals.     

Improved in silico prediction of carcinogenic potency (TD50) and the risk specific dose (RSD) adjusted Threshold of Toxicological Concern (TTC) for genotoxic chemicals and pharmaceutical impurities

The Threshold of Toxicological Concern (TTC) is a level of exposure to a genotoxic impurity that is considered to represent a negligible risk to humans. The TTC was derived from the results of rodent carcinogenicity TD50 values that are a measure of carcinogenic potency. The TTC currently sets a default limit of 1.5 μg/day in food contact substances and pharmaceuticals for all genotoxic impurities without carcinogenicity data. Bercu et al. (2010) used the QSAR predicted TD50 to calculate a risk specific dose (RSD) which is a carcinogenic potency adjusted TTC for genotoxic impurities. This promising approach is currently limited by the software used, a combination of MC4PC (www.multicase.com) and a Lilly Inc. in-house software (VISDOM) that is not available to the public. In this report the TD50 and RSD were predicted using a commercially available software, SciQSAR (formally MDL-QSAR, www.scimatics.com) employing the same TD50 training data set and external validation test set that was used by Bercu et al. (2010). The results demonstrate the general applicability of QSAR predicted TD50 values to determine the RSDs for genotoxic impurities and the improved performance of SciQSAR for predicting TD50 values.     

Severe onychodystrophy caused by allergic contact dermatitis to acrylates in artificial nails

Acrylic resin monomers, especially acrylates and methacrylates, are well-known sensitizers responsible for allergic contact dermatitis mainly in the occupational setting. The most frequently affected professionals are dentists, orthopedic surgeons, manicurists, painting industry and fiberglass workers. The authors report the case of a 39-year-old healthy woman, a secretary, who developed severe onychodystrophy of all fingers, 1 week after the application of sculptured acrylic nails.     

Improvement of the Cramer classification for oral exposure using the database TTC RepDose--a strategy description

The present report describes a strategy to refine the current Cramer classification of the TTC concept using a broad database (DB) termed TTC RepDose. Cramer classes 1–3 overlap to some extent, indicating a need for a better separation of structural classes likely to be toxic, moderately toxic or of low toxicity.Groups of structurally similar compounds of high toxicity in Cramer class 1 and of moderate to low toxicity in Cramer class 3 were identified and reassigned to the appropriate Cramer class according to their observed toxicological potency in in vivo studies. This refinement results in a better discrimination of Cramer classes 1 and 3 and an increased number of substances in Cramer class 2. The TTC values are 8.7 μmol/person/d (class 1), 6.72 μmol/person/d (class 2) and 0.28 μmol/person/d (class 3). Assuming a median molecular weight of 220 g/mol for the compounds of the TTC RepDose DB, the corresponding TTC values are 1930, 1478 and 63 μg/person/d for classes 1, 2 and 3 respectively. The derived thresholds are close to the TTC values initially proposed by Munro with 1800, 540 and 90 μg/person/d for classes 1, 2 and 3 respectively. Additional structural classes are discussed with a view to further refinement of the current Cramer classification scheme.     

Periocular allergic contact dermatitis following topical Mitomycin C eye drop application

A 63-year-old women had an extensive limbal papilliform tumoural lesion of her left eye. Mitomycin C (MMC) was applied to thearea at a dose of 0.2?mg/ml after total surgical excision of the lesion. The lesion was diagnosed as invasive squamous cell carcinoma on histopathology and topical 0.02% MMC was prescribed four times daily to the left eye. A severe periocular contact dermatitis of the left eye developed two days after starting MMC. The patch test result was positive. The periocular dermatitis resolved after discontinuation of the topical MMC and treatment with a topical corticosteroid.     

Refinement of the Dermal Sensitisation Threshold (DST) approach using a larger dataset and incorporating mechanistic chemistry domains

An essential step in ensuring the toxicological safety of ingredients in consumer products is the evaluation of their skin sensitising potential. Where skin exposure is low, it is possible to conduct a risk assessment using the Dermal Sensitisation Threshold (DST), a process similar to that of the Threshold of Toxicological Concern. This paper describes work building on that previously published, whose aim was to produce a more robust tool for assessing the safety of consumer products. This consisted of expanding the Local Lymph Node Assay dataset used to define the original DST and classifying chemicals in the dataset according to their mechanistic chemistry domains. A DST of 900μg/cm(2) was derived for chemicals classified as non-reactive and non-proreactive. This value was benchmarked against human potency data for 58 fragrance allergens and was lower than the measured No Expected Sensitisation Levels for those classified as non-reactive. Use of this DST will help to eliminate the need for animal testing of non-reactive and non-proreactive chemicals where skin exposure is sufficiently low. For chemicals where a Quantitative Risk Assessment based on the DST does not give an adequate margin of safety, and those classified as reactive, a case-by-case risk assessment will be required.