Skin sensitization quantitative risk assessment: A review of underlying assumptions

Basketter, David A.; Safford, Bob

doi:10.1016/j.yrtph.2015.11.013

Cited by 77 publications

(53 citation statements)

References 86 publications

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“…The validity of the current version of the QRA has previously been questioned, as well as concerns raised that the model fails to assess aggregate exposures to fragrance chemicals, which occurs commonly . The fragrance industry has recently proposed several changes to the safety factors applied in the QRA, which are used to calculate acceptable exposure levels to fragrance allergens in consumer products . However, the resulting proposed acceptable exposure levels seem very similar to the ones derived from the original QRA and the issue of aggregate exposure is still not addressed.…”

Section: Discussionmentioning

confidence: 99%

Trends in contact allergy to fragrance mix I in consecutive Danish patients with eczema from 1986 to 2015: a cross-sectional study

2017

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Section: Discussionmentioning

confidence: 99%

Trends in contact allergy to fragrance mix I in consecutive Danish patients with eczema from 1986 to 2015: a cross-sectional study

2017

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“…The breadth of MW values within this set of 14 substances clearly supports the premise that penetration through the stratum corneum is not a rate-determining factor in driving sensitization potency. This is supported, albeit indirectly, in a recent review by Basketter and Safford (2016) who discussed sources of uncertainty in skin sensitization risk assessment, including the influence of skin condition. Facilitating skin penetration with a compromised skin barrier should result in a greater incidence of skin sensitization if penetration were a rate-determining factor.…”

Section: Discussionmentioning

confidence: 77%

What determines skin sensitization potency: Myths, maybes and realities. The 500 molecular weight cut‐off: An updated analysis

Fitzpatrick

Roberts

Patlewicz

2016

J of Applied Toxicology

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It is widely accepted that substances must have a molecular weight (MW) < 500 to penetrate effectively through the skin to induce sensitization. Roberts et al. (2012. Contact Dermatitis 68: 32-41) evaluated a data set of 699 substances taken from the TIMES-SS expert system and identified that of the 13 substances with a MW > 500, five were sensitizers. This provided good evidence to refute such a MW 500 threshold. While Roberts et al. (2012) made a convincing case that the MW > 500 cut-off was not a true requirement for sensitization, the number of counter examples identified were too few to draw any statistical conclusions. This updated analysis systematically interrogated a large repository of sensitization information collected under the EU REACH regulation. A data set of 2904 substances that had been tested for skin sensitization, using guinea pigs and/or mice were collected. The data set contained 197 substances with a MW> 500; 33 of these were skin sensitizers. Metal containing complexes, reaction products and mixtures were excluded from further consideration. The final set of 14 sensitizers substantiated the original findings. The study also assessed whether the same reaction chemistry principles established for low MW sensitizers applied to chemicals with a MW > 500. The existing reaction chemistry considerations were found appropriate to rationalize the sensitization behaviour of the 14 sensitizers with a MW > 500. The existence of the MW 500 threshold, based on the widespread misconception that the ability to penetrate efficiently the stratum corneum is a key determinant of skin sensitization potential and potency, was refuted. Copyright © 2016 John Wiley & Sons, Ltd.

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“…It is known that there can be large inter-individual differences in response to a chemical exposure. However, since expected no-effect sensitization levels (NESILs) are determined at a dose below the sensitization threshold, much of this variability is already taken into account 96 . Despite this high variability, we modeled these data (see QSAR modeling section) and analyzed the predictions for these compounds when they were in the external folds.…”

Section: Resultsmentioning

confidence: 99%

“…111 Due to the high inter-individual variability of human tests, multiple sources of exposure must be evaluated for quantitative risk assessment of skin sensitization. 96 It has been shown that consensus prediction typically affords models of higher accuracy. 91,112,113 Thus, we decided to combine QSAR predictions and LLNA assessment to predict human skin sensitization.…”

Section: Resultsmentioning

confidence: 99%

QSAR models of human data can enrich or replace LLNA testing for human skin sensitization

et al. 2016

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Skin sensitization is a major environmental and occupational health hazard. Although many chemicals have been evaluated in humans, there have been no efforts to model these data to date. We have compiled, curated, analyzed, and compared the available human and LLNA data. Using these data, we have developed reliable computational models and applied them for virtual screening of chemical libraries to identify putative skin sensitizers. The overall concordance between murine LLNA and human skin sensitization responses for a set of 135 unique chemicals was low (R = 28-43%), although several chemical classes had high concordance. We have succeeded to develop predictive QSAR models of all available human data with the external correct classification rate of 71%. A consensus model integrating concordant QSAR predictions and LLNA results afforded a higher CCR of 82% but at the expense of the reduced external dataset coverage (52%). We used the developed QSAR models for virtual screening of CosIng database and identified 1061 putative skin sensitizers; for seventeen of these compounds, we found published evidence of their skin sensitization effects. Models reported herein provide more accurate alternative to LLNA testing for human skin sensitization assessment across diverse chemical data. In addition, they can also be used to guide the structural optimization of toxic compounds to reduce their skin sensitization potential.

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Skin sensitization quantitative risk assessment: A review of underlying assumptions

Cited by 77 publications

References 86 publications

Trends in contact allergy to fragrance mix I in consecutive Danish patients with eczema from 1986 to 2015: a cross-sectional study

Trends in contact allergy to fragrance mix I in consecutive Danish patients with eczema from 1986 to 2015: a cross-sectional study

What determines skin sensitization potency: Myths, maybes and realities. The 500 molecular weight cut‐off: An updated analysis

QSAR models of human data can enrich or replace LLNA testing for human skin sensitization

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