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Publications (4)9.36 Total impact

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    A.M. Api · J. Lalko · R. Safford · D. Roberts · R. Parakhia

    Full-text · Article · Oct 2015 · Toxicology Letters
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    Robert J. Safford · Anne Marie Api · David W. Roberts · Jon F. Lalko
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    ABSTRACT: 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/cm(2) 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 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. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Apr 2015 · Regulatory Toxicology and Pharmacology
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    David W. Roberts · Anne Marie Api · Robert J. Safford · Jon F. Lalko
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    ABSTRACT: An essential step in ensuring the toxicological safety of chemicals used in consumer products is the evaluation of their skin sensitising potential. The sensitising potency, coupled with information on exposure levels, can be used in a Quantitative Risk Assessment (QRA) to determine an acceptable level of a given chemical in a given product. Where consumer skin exposure is low, a risk assessment can be conducted using the Dermal Sensitisation Threshold (DST) approach, avoiding the need to determine potency experimentally. Since skin sensitisation involves chemical reaction with skin proteins, the first step in the DST approach is to assess, on the basis of the chemical structure, whether the chemical is expected to be reactive or not. Our accompanying publication describes the probabilistic derivation of a DST of 64 μg/cm(2) for chemicals assessed as reactive. This would protect against 95% of chemicals assessed as reactive, but the remaining 5% would include chemicals with very high potency. Here we discuss the chemical properties and structural features of high potency sensitisers, and derive an approach whereby they can be identified and consequently excluded from application of the DST. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Mar 2015 · Regulatory Toxicology and Pharmacology
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    ABSTRACT: Based on chemical, cellular, and molecular understanding of dermal sensitization, an exposure-based quantitative risk assessment (QRA) can be conducted to determine safe use levels of fragrance ingredients in different consumer product types. The key steps are: (1) determination of benchmarks (no expected sensitization induction level (NESIL)); (2) application of sensitization assessment factors (SAF); and (3) consumer exposure (CEL) calculation through product use. Using these parameters, an acceptable exposure level (AEL) can be calculated and compared with the CEL. The ratio of AEL to CEL must be favorable to support safe use of the potential skin sensitizer. This ratio must be calculated for the fragrance ingredient in each product type. Based on the Research Institute for Fragrance Materials, Inc. (RIFM) Expert Panel’s recommendation, RIFM and the International Fragrance Association (IFRA) have adopted the dermal sensitization QRA approach described in this review for fragrance ingredients identified as potential dermal sensitizers. This now forms the fragrance industry’s core strategy for primary prevention of dermal sensitization to these materials in consumer products. This methodology is used to determine global fragrance industry product management practices (IFRA Standards) for fragrance ingredients that are potential dermal sensitizers. This paper describes the principles of the recommended approach, provides detailed review of all the information used in the dermal sensitization QRA approach for fragrance ingredients and presents key conclusions for its use now and refinement in the future.
    Full-text · Article · Oct 2008 · Regulatory Toxicology and Pharmacology