An interim internal Threshold of Toxicologic Concern (iTTC) for chemicals in consumer products, with support from an automated assessment of ToxCast™ dose response data.

Additional non-animal methods are urgently needed to meet regulatory and animal welfare goals. TTC is a broadly used risk assessment tool. TTC based on external dose has limited utility for multi-route exposure and some types of structure activity relationship assessments. An internal TTC (iTTC), where thresholds are based on blood concentration, would extend the applicability of TTC. While work is on-going to develop robust iTTC thresholds, we propose an interim conservative iTTC. Specifically, an interim iTTC of 1 µM, supported by the published experience of the pharmaceutical industry, a literature review of non-drug chemical/receptor interactions, and analysis of ToxCast™ data. ToxCast™ data were used to explore activity versus the 1 µM interim iTTC and recommendations for the analysis and interpretation of HTS data. Test concentration-based points of departure were classified to identify quality of fit to the Hill Model. We identified, for exclusion from the approach, estrogen receptor and androgen receptor targets as potent chemical/receptor interactions potentially associated with low dose exposure to non-pharmaceutical active ingredients in addition to the original TTC exclusions. With these exclusions, we conclude that a 1 µM plasma concentration is unlikely to be associated with significant biological effects from chemicals not intentionally designed for biological activity.

Cleaning and asthma: A systematic review and approach for effective safety assessment.

Research indicates a correlative relationship between asthma and use of consumer cleaning products. We conduct a systematic review of epidemiological literature on persons who use or are exposed to cleaning products, both in occupational and domestic settings, and risk of asthma or asthma-like symptoms to improve understanding of the causal relationship between exposure and asthma. A scoring method for assessing study reliability is presented. Although research indicates an association between asthma and the use of cleaning products, no study robustly investigates exposure to cleaning products or ingredients along with asthma risk. This limits determination of causal relationships between asthma and specific products or ingredients in chemical safety assessment. These limitations, and a lack of robust animal models for toxicological assessment of asthma, create the need for a weight-of-evidence (WoE) approach to examine an ingredient or product's asthmatic potential. This proposed WoE method organizes diverse lines of data (i.e., asthma, sensitization, and irritation information) through a systematic, hierarchical framework that provides qualitatively categorized conclusions using hazard bands to predict a specific product or ingredient's potential for asthma induction. This work provides a method for prioritizing chemicals as a first step for quantitative and scenario-specific safety assessments based on their potential for inducing asthmatic effects. Acetic acid is used as a case study to test this framework.

A tiered asthma hazard characterization and exposure assessment approach for evaluation of consumer product ingredients.

Asthma is a complex syndrome with significant consequences for those affected. The number of individuals affected is growing, although the reasons for the increase are uncertain. Ensuring the effective management of potential exposures follows from substantial evidence that exposure to some chemicals can increase the likelihood of asthma responses. We have developed a safety assessment approach tailored to the screening of asthma risks from residential consumer product ingredients as a proactive risk management tool. Several key features of the proposed approach advance the assessment resources often used for asthma issues. First, a quantitative health benchmark for asthma or related endpoints (irritation and sensitization) is provided that extends qualitative hazard classification methods. Second, a parallel structure is employed to include dose-response methods for asthma endpoints and methods for scenario specific exposure estimation. The two parallel tracks are integrated in a risk characterization step. Third, a tiered assessment structure is provided to accommodate different amounts of data for both the dose-response assessment (i.e., use of existing benchmarks, hazard banding, or the threshold of toxicological concern) and exposure estimation (i.e., use of empirical data, model estimates, or exposure categories). Tools building from traditional methods and resources have been adapted to address specific issues pertinent to asthma toxicology (e.g., mode-of-action and dose-response features) and the nature of residential consumer product use scenarios (e.g., product use patterns and exposure durations). A case study for acetic acid as used in various sentinel products and residential cleaning scenarios was developed to test the safety assessment methodology. In particular, the results were used to refine and verify relationships among tiered approaches such that each lower data tier in the approach provides a similar or greater margin of safety for a given scenario.

Keratocystic odontogenic tumors and Carnoy's solution: results and complications assessment.

OBJECTIVE: Keratocystic odontogenic tumors (KOTs) can be treated with Carnoy's solution, although this treatment modality is not free from complications. It is important to verify the incidence of complications after the use of Carnoy's solution and compare these with the literature. MATERIALS AND METHODS: This study verified the effects of a complementary treatment for KOTs and assessed the incidence of such complications as recurrence, infection, sequestrum formation, mandibular fracture, dehiscence, and neuropathy. RESULTS: Twenty-two KOTs treated with Carnoy's solution combined with peripheral ostectomy were included, and the follow-up period varied from 12 to 78months with a mean of 42.9months. Complications included recurrence (4.5%), dehiscence (22.7%), infection (4.5%), and paresthesia (18.2%). No difference was found among lesions associated (9.1%) or not (0%) with nevoid basal cell carcinoma syndrome (P>0.05). Dehiscence was influenced by marsupialization (P<0.05), and paresthesia was observed exclusively in cases of mandibular canal fenestration (P<0.01). CONCLUSIONS: Complementary treatment with Carnoy's solution and peripheral ostectomy appear to provide efficient treatment for KOTs. Complications originating from the use of the solution are less frequent and less serious than complications associated with cryotherapy. Neuropathy seems to be related to direct contact between the solution and the epineurium.

Topographic and radiographic profile assessment of dental erosion--Part I: Effect of acidulated carbonated beverages on human dentition.

Evidence-based case reports and epidemiologic surveys have indicated an association between dental erosion and high consumption of acidulated carbonated beverages (ACBs). This study sought to monitor the effect of exposure to ACBs on the topography and geometrical profile of disassociated human dentition. Two representatives of ACBs, caramelized (ACCB) and non-caramelized (AN-CCB), were evaluated along with control liquids. Following exposure to the fluids, qualitative assessment of topographic changes and quantitative analysis of digitized serial radiographic tracings were performed at four-week intervals for 20 weeks. Within the controlled perimeters of this in vitro test, the erosive effects of ACBs were closely similar but were lower than those caused by acetic acid (control fluid). These effects were indicated by changes in enamel topography (such as color, translucency, texture, and integrity) as well as reduction in specimen profile parameters. This amounted to an average weekly reduction in cusp tip height, a loss of cervical enamel, a reduction of enamel cap height, and reduction of crown radius for the ACBs and acetic acid.

[Hygienic assessment of components of smoking fume]. / Gigienicheskaia otsenka komponentov koptil'nogo dyma.

Analyzing the chemical composition of smoking fume has indicated that maximum allowable concentrations (MACs) have been established for 50 of 400 well-known compounds, working area MACs were standardized for 42 of the 50 compounds, the maximum single and daily average concentrations were standardized for 34 and 30 compounds, respectively. All standards were established for 25 compounds. Despite the fact that there a large list of MACs, it is difficult to calculate the objective hygienic risk of smoking smoke since 32 compounds are contained in traces. Hygienic assessment of fume discharges from the smoking chamber by taking into account their mass and MACs demonstrated that phenols, carbonyl compounds, acids, and benz(a)pyrene which should be used to work out the unified hygienic standard are of the greatest importance.

Application of a 4-h human patch test method for comparative and investigative assessment of skin irritation.

A human 4-h patch test has recently been developed for testing the irritation hazard potential of chemicals. The original method was developed for comparative irritation assessments relative to benchmark irritants using simple statistical tests. In this context, the method has been shown to be robust in intralaboratory testing over time. Recent interlaboratory testing has also established the consistency of the method in assessment of the relative irritation potential of selected chemicals. These data help to position the method as a suitable replacement for animal test methods in assessment of skin irritation hazard. In addition, the method has great utility for investigating different parameters of clinical skin irritation. Using kinetic response patterns and curve fitting analysis, we have compared the relative irritation potential of chemicals in greater detail, using as a basis the time required for test subjects to respond as well as the incidence of positive responses. Also, using the response to 20% sodium dodecyl sulfate (SDS) as a benchmark, we've been able to examine the intersubject variation in clinical skin irritation responses. In general, subjects most reactive to 20% SDS, in terms of the exposure time required to produce a positive response, were relatively more sensitive to a 2nd irritant chemical as well. However, this was not an absolute correlation in that some test subjects showed divergent patterns of response. The method was also used to compare directly the relative skin reactivity of different populations, based on race (Caucasian versus Asian) or on neurosensory skin sensitivity. Our results using this acute exposure test method indicate little difference in visually assessed skin irritation among these diverse human subpopulations.