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.

Challenges in working towards an internal threshold of toxicological concern (iTTC) for use in the safety assessment of cosmetics: Discussions from the Cosmetics Europe iTTC Working Group workshop.

The Threshold of Toxicological Concern (TTC) is an important risk assessment tool which establishes acceptable low-level exposure values to be applied to chemicals with limited toxicological data. One of the logical next steps in the continued evolution of TTC is to develop this concept further so that it is representative of internal exposures (TTC based on plasma concentration). An internal TTC (iTTC) would provide threshold values that could be utilized in exposure-based safety assessments. As part of a Cosmetics Europe (CosEu) research program, CosEu has initiated a project that is working towards the development of iTTCs that can be used for the human safety assessment. Knowing that the development of an iTTC is an ambitious and broad-spanning topic, CosEu organized a Working Group comprised a balance of multiple stakeholders (cosmetics and chemical industries, the EPA and JRC and academia) with relevant experience and expertise and workshop to critically evaluate the requirements to establish an iTTC. Outcomes from the workshop included an evaluation on the current state of the science for iTTC, the overall iTTC strategy, selection of chemical databases, capture and curation of chemical information, ADME and repeat dose data, expected challenges, as well as next steps and ongoing work.

Tissue distribution of 20 nm, 100 nm and 1000 nm fluorescent polystyrene latex nanospheres following acute systemic or acute and repeat airway exposure in the rat.

Understanding tissue distribution and clearance of nanomaterials following different routes of exposure is needed for risk assessment. F344 female rats received single or multiple exposures to 20 nm, 100 nm or 1000 nm latex fluorospheres by intravenous (i.v.) injection or oral pharyngeal aspiration into the airways. The presence of fluorospheres in tissues was assessed up to 90-120 days after the final dose. Blood, perfusion fluid, bone marrow, brain, eyes, feces, gut, heart, kidney, liver, lung, muscle, skin, spleen, thymus, tongue, urine and uterus plus ovaries were collected for analysis. Liver, spleen and lung were the greatest tissue depots for all particles following i.v. injection. The proportion of 100 nm and 1000 nm but not 20 nm spheres significantly increased in the spleen over time. Lung was the greatest tissue depot for all particles following single or repeat airway exposure. Greater than 95% of 1000 nm spheres that were recovered were in the lung in contrast to 70-80% of 20 nm spheres or 89-95% of 100 nm spheres. All 3 sizes were found in gut or gut+feces 1-7 days after lung exposure. The thymus was the largest extra-pulmonary depot for the particles; up to 25% of recovered 20 nm particles were in the thymus up to 4 months after exposure compared to 6% of 100 nm particles and 1-3% of 1000 nm particles. A small proportion of 20 nm particles were detected in kidney following both acute and repeat airway exposure. Low numbers of particles were found in the circulation (blood, perfusion), bone marrow, brain, heart, liver and spleen but not in eye, muscle, skin, tongue, ovaries, uterus or urine. These data show that the tissue targets of nano- and micron-sized spheres are very similar whether exposure occurs systemically or via the airways while the proportion of particles in some tissues and tissue clearance varies based on particle size.

Experimental synchronization of chaos in diode lasers with polarization-rotated feedback and injection.

We demonstrate experimental chaos synchronization between two chaotic semiconductor lasers subjected to polarization-rotated optical feedback and unidirectional injection. This system allows high-quality synchronization to be obtained between dissimilar lasers in a wide range of chaotic operating regimes. Another feature of this system is its operation at high characteristic frequencies, taking advantage of all-optical implementation. Time series and RF spectra showing synchronization are confirmed by high correlation coefficients in excess of 0.85.

Quantitative risk assessment for the induction of allergic contact dermatitis: uncertainty factors for mucosal exposures.

The quantitative risk assessment (QRA) paradigm has been extended to evaluating the risk of induction of allergic contact dermatitis from consumer products. Sensitization QRA compares product-related, topical exposures to a safe benchmark, the sensitization reference dose. The latter is based on an experimentally or clinically determined 'no observable adverse effect level' (NOAEL) and further refined by incorporating 'sensitization uncertainty factors' (SUFs) that address variables not adequately reflected in the data from which the threshold NOAEL was derived. A critical area of uncertainty for the risk assessment of oral care or feminine hygiene products is the extrapolation from skin to mucosal exposures. Most sensitization data are derived from skin contact, but the permeability of vulvovaginal and oral mucosae is greater than that of keratinized skin. Consequently, the QRA for some personal products that are exposed to mucosal tissue may require the use of more conservative SUFs. This article reviews the scientific basis for SUFs applied to topical exposure to vulvovaginal and oral mucosae. We propose a 20-fold range in the default uncertainty factor used in the contact sensitization QRA when extrapolating from data derived from the skin to situations involving exposure to non-keratinized mucosal tissue.