Name: This is what we do. | RIFM's 55th Annual Meeting
Start: 08/09/2021 12:00 PM +00:00
End: 09/09/2021 04:00 PM +00:00

The U-SENS&trade; assay was developed to address the third key event of the skin sensitization adverse outcome pathway (AOP), dendritic cell (DC) activation, and is described in OECD test guideline 442E, Annex II. We aimed to determine how well the potential of fragrance ingredients to activate dendritic cells, measured by U-SENS&trade;, compared to the sensitization potential determined by weight of evidence (WoE) from combined historical in vivo (human and animal) and in vitro data.&nbsp;

U-SENS Assay to Assess Skin Sensitization Potential

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Innovative scientific approaches can help save animal liveswithout breaking the bank.

Genotoxicity Animal-Alternative Approaches

Analyzing complex mixtures for bioaccumulation potential using the trout in vitro metabolism assay (OECD TG 319A and 319B): a case study, fir oil (pine oil) a Natural Complex Substance (NCS).

NCS Bioaccumulation: A Case Study

The RIFM research programs focus on New Approach Methodologies (NAMs)

RIFM Research Programs Focus on New Approach Methodologies (NAMs)

As a part of the overarching goal of successfully implementing animal-alternative testing, RIFM respiratory research is establishing a list of standard chemicals of known respiratory sensitizers. These &ldquo;Gold Standard&rdquo; chemicals are proposed as suitable positive controls for test model and test method development to study respiratory sensitization.

Respiratory Sensitizers as a “Gold Standard”

Some fragrance ingredients may have the potential to induce skin sensitization in humans but can still be safely formulated into consumer products. Quantitative risk assessment (QRA) for dermal sensitization is required to determine safe levels at which potential skin sensitizers can be incorporated into consumer products. The no expected sensitization induction level or NESIL is the point of departure for the dermal sensitization QRA. Sensitization assessment factors (SAFs) are applied to the NESIL to determine acceptable exposure levels at which no skin sensitization induction would be expected in the general population. The purpose of this work is to elucidate the key steps involved in the derivation of the NESIL for use in the QRA of fragrance ingredients. Generally, this process involves, collating and analyzing all available historical data on a given fragrance ingredient, determining the chemical&rsquo;s potency, and finally deriving a weight of evidence (WoE) NESIL. When a material is determined to present a skin sensitization hazard, the WoE NESIL is set based on a NOEL (no observable effect level) generated from a confirmation of no induction in humans (CNIH) study. When limited or no information is available on a chemical, a read-across may be used to fill the data gap or the dermal sensitization threshold (DST) approach may be applied where appropriate before further testing is considered. We provide a few case studies illustrating how the WoE approach is applied to generate a NESIL for fragrance ingredients. These case studies demonstrate how target data, read-across, or the DST are considered when setting a NESIL and also highlight the importance of using a WoE approach to set a NESIL. We outline the process as it currently stands at the Research Institute for Fragrance Materials (RIFM), but it is dynamic and is bound to change with evolving science as new approach methodologies (NAMs) are actively incorporated.

NESIL Derivation for the Dermal Quantitative Risk Assessment

RIFM Safety Assessments are based on risk, which integrates both hazard and exposure.

Hazard vs Risk: A Case Study Using BMHCA

Objective: Develop a new method of hazard assessment for NCS2 with a fractionation approach.

CHANCES 2: Environmental Toxicity Assessment of Natural Complex Substances Type 2 (NCS2)

Safety assessment of Natural Complex Substances (NCS) is similar to discrete fragrance materials; all of the same endpoints are evaluated. A series of decision trees, reflecting advances in risk assessment approaches of mixtures and toxicological methodologies, follow a tiered approach for each endpoint using a 4-step process with testing only as a last resort: 1) evaluate available data on NCS, 2) verify whether Threshold of Toxicological Concern (TTC) can be applied, 3) verify whether the NCS risk assessment can be achieved on a component basis, 4) determine whether data must be generated.&nbsp;

NCS Process - The RIFM Approach to Evaluating Natural Complex Substances

Several New Approach Methods for hazard identification of skin sensitizers have been developed and incorporated as OECD Test Guidelines. However, the methods for potency assessment are still lacking. GARDskin (OECD TGP 4.106) was initially developed to identify skin sensitizers by monitoring transcriptional patterns of a biomarker signature in a dendritic like cell line. The predictive capacity of GARDskin has been demonstrated previously, with 95.8% accuracy, 91.7% positive predictive value, and 100.0% negative predictive value (1 false positive, n 24) (Johansson, Gradin et al. 2019). To derive potency information, a strategy based on dose response measurements in GARDskin, referred to as the GARDskin Dose Response assay, has recently been proposed. The readout of the assay corresponds to the lowest concentration required to exceed the binary classification threshold in GARDskin. This concentration correlates with local lymph node assay (LLNA) EC3 and human no observed effect level (NOEL) values and linear regression models have been established to exploit these relationships for potency predictions. In this blinded study, 12 fragrance materials (10 very weak sensitizers and 2 weak sensitizers) were evaluated in GARDskin Dose Response. Results were evaluated by comparing predicted values to the reference potency categories. Three of the very weak sensitizers were predicted as non-sensitizers by GARDskin Dose Response. For the remaining nine materials which were predicted as sensitizers, the predicted EC3 and NOEL values closely approximated the reference data for most materials. Based on results from this dataset, GARDskin Dose Response appears useful for potency assessment for weak sensitizers and may constitute a promising strategy for deriving a point of departure for quantitative risk assessments.

Using GARDskin Dose Response Assay for Skin Sensitization Potency Assessments of Fragrance Materials

Using the Threshold of Toxicological Concern (TTC) as an exposure-based waiving approach is an important animal-alternative technique.

Respiratory TTC to Save Animal Lives

Currently, several validated non-animal methods are available to assess the skin sensitization potential of chemicals. Each of these assays addresses a specific key event in the adverse outcome pathway (OECD, 2012). The direct peptide reactivity assay (DPRA) and amino acid derivative reactivity assay (ADRA) are validated to test the chemical&rsquo;s ability to activate the molecular initiating event (OECD TG442C). When used in combination with other non-animal methods, DPRA has been shown to be valuable in hazard identification of skin sensitizers. However, determining the potency of skin sensitizers using non-animal methods remains a challenge. Recently, it was suggested that kinetic DPRA (kDPRA) could be utilized to assign the skin sensitization potency class of a chemical (Wareinget al., 2017). In this modification from the standard DPRA, the chemical&rsquo;s reaction with a model peptide are measured at multiple concentrations and multiple time points. A rate constant for this reaction has been shown to be a good predictor of the skin sensitization potency (Natsch et al., 2020). Herein, we report data and analysis of 60 fragrance ingredients (49 sensitizers and 11 non-sensitizers) in the kDPRAmethod, in comparison with existing animal and human data. For this dataset, 12 of the 49 sensitizers and 2 of the 11 non-sensitizers exhibited peptide reactivity. The 14 materials that have shown peptide reactivity were predicted as stronger sensitizers, when compared to the animal and human data for this dataset.

Kinetic DPRA to Assess Skin Sensitization Potential

Seven materials will be removed from RIFM&rsquo;s Safety Assessment program on January 1, 2022, unless RIFM receives missing samples and concentration survey data.

Not Supported List

Reliable human potency data is necessary for appropriate evaluation of new non-animal methods for skin sensitization potency prediction. The potency information is also critical for the quantitative risk assessment. Previously, human skin sensitization potency of fragrance materials was derived primarily using human data (Api et al., 2017). However, human testing is not typically conducted to explore the dose-response of a chemical. Rather, the human testing is conducted at a single dose that is expected to be safe. For this reason, the No Observed Effect Level (NOEL) from the human test can be close to, or well below, the threshold of the induction of sensitization. This means that human data alone may not correlate well with the actual potency of a given material. Therefore, we propose a Weight of Evidence (WoE) approach for potency categorization, where all existing data should be considered collectively. To demonstrate this approach, human, animal, in vitro, in chemico, and in silico data on 106 fragrance materials were evaluated to set skin sensitization potency categories (Extreme, Strong, Moderate, Weak, Very Weak and Non-Sensitizer). None was considered an extreme sensitizer, while 6, 23, 41, and 26 materials were categorized as strong, moderate, weak, and very weak sensitizers, respectively. Ten materials lacked evidence for the induction of skin sensitization. The skin sensitization potency categories for fragrance materials based on the WoE approach are provided in this work. The WoE categories can serve as references for evaluation of the new non-animal methods, as well as for the quantitative risk assessment.

Skin Sensitization Potential: Weight of Evidence Approach

At the Research Institute of Fragrance Materials (RIFM), our role is to ensure the safe use of fragrance materials for the general population, while being proactive in looking for alternatives to animal testing. Zebrafish has been a well-known model for developmental toxicity in the past few decades. Biobide&rsquo;s Teratotox Assay analyzes zebrafish embryo at 2- and 4-days post fertilization (dpf) for developmental toxicity by looking at specific malformations. A blinded study was conducted on 10 fragrance materials which already had in vivo developmental toxicity data. Based on LC50 (mortality) and EC50 (number of abnormal embryos), a teratogenic index (TI) was calculated for all the 10 materials. According to the Biobide&rsquo;s Teratotox Assay, a TI value of above 2 is considered to be likely teratogenic.

Zebrafish Model for Developmental Toxicity May Help to Predict Potential Toxicity and Prioritize Testing

Business Meeting, Awards, Member Services &amp; Communications Updates, Science Roundtable Discussion

Full Agenda

Speakers.css-113yu86{margin:0;font-size:1.4rem;font-weight:500;line-height:1.5;color:#485b7b;font-family:'Poppins',sans-serif;margin-left:0.8rem;}36 Speakers

Aurelia Lapczynski

Mihir Daté

Danielle Botelho

Anne Marie Api

Chaitra Deodhar

Kaushal Joshi

Manoj Kumar

Maura Lavelle

Isabelle Lee

Holger Moustakas

Mihwa Na

Gretchen Ritacco

Nikaeta Sadekar

Dan Selechnik

Yax Thakkar

Faiz Siddiqi

Mary Mircovich

Mary Ann Cancellieri

Leah Jones

Gary Sullivan

James Romine

Steven Manzi

Nancy Nowinski

Jill Bohan

Meghan Barreto

Kimberly Arencibia

Tracy Foley

Julie Blanker

Christen Sachse-Vasquez

Olive Chon

Robby Gunawan

Shawn Blythe

Tobey Marzouk

Andreas Natsch

Ian Walsh

Bob Weinstein

Science Posters.css-g39vo8{margin:0;font-size:1.4rem;font-weight:500;line-height:1.5;color:#485b7b;font-family:'Poppins',sans-serif;color:#ffffff;margin-left:0.8rem;font-weight:400;}16 Science Posters