The Experts below are selected from a list of 67452 Experts worldwide ranked by ideXlab platform
Ian Kimber - One of the best experts on this subject based on the ideXlab platform.
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potency values from the local Lymph Node assay application to classification labelling and risk assessment
Regulatory Toxicology and Pharmacology, 2010Co-Authors: Scott E Loveless, Ian R. Jowsey, Petra Kern, A Gamer, L J Lea, Eric Debruyne, Ian Kimber, Anne Marie Api, Rene W R Crevel, P LloydAbstract:Abstract Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local Lymph Node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: ‘extreme’, ‘strong’, ‘moderate’ and ‘weak’. Since draining Lymph Node Cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.
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potency values from the local Lymph Node assay application to classification labelling and risk assessment
Regulatory Toxicology and Pharmacology, 2010Co-Authors: Scott E Loveless, Ian R. Jowsey, Petra Kern, A Gamer, L J Lea, Eric Debruyne, Ian Kimber, Anne Marie Api, Rene W R Crevel, P LloydAbstract:Abstract Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local Lymph Node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: ‘extreme’, ‘strong’, ‘moderate’ and ‘weak’. Since draining Lymph Node Cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.
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induced changes in total serum ige concentration in the brown norway rat potential for identification of chemical respiratory allergens
Journal of Applied Toxicology, 2002Co-Authors: E V Warbrick, Rebecca J Dearman, Ian KimberAbstract:A variety of chemicals can cause sensitization of the respiratory tract and occupational asthma that may be associated with IgE antibody production. Topical exposure to chemical respiratory allergens such as trimellitic anhydride (TMA) has been shown previously to induce increases in the total serum concentration of IgE in BALB/c strain mice. Contact allergens such as 2,4-dinitrochlorobenzene (DNCB), which apparently lack respiratory sensitizing potential, fail to provoke similar changes. However, it became apparent with time that there was some inter-animal variation in constitutive and inducible IgE levels. We have now examined the influence of topical exposure to TMA and DNCB on serum IgE levels in the Brown Norway (BN) rat. Such animals can be bled serially and thus it is possible to perform longitudinal analyses of changes in serum IgE concentration. The kinetics of IgE responses therefore can be followed on an individual animal basis, allowing discrimination between transient and sustained increases in serum IgE concentration. Rats (n = 5) were exposed on shaved flanks to 50% TMA, to 1% DNCB (concentrations that elicit comparable immune activation with respect to draining Lymph Node Cellularity and proliferation) or to vehicle alone. Total IgE was measured by enzyme-linked immunosorbent assay in serum samples taken prior to and 14-42 days following initial exposure. Those animals having high pre-existing IgE levels (>1.0 microg ml(-1)) were excluded from subsequent analyses. The levels of serum IgE in the majority of rats exposed to DNCB or vehicle alone remained relatively stable throughout the duration of all the experiments conducted, although some animals displayed transient increases in serum IgE. Only TMA treatment was associated with a significant and sustained increase in the level of serum IgE in the majority of experiments. The elevated concentrations of IgE induced by topical exposure to TMA are persistent, the results reported here demonstrating that induced changes in IgE are maximal or near maximal at approximately 35 days, with a significant increase in IgE demonstrable for at least 42 days following the initiation of exposure. Interestingly, although TMA and DNCB at the test concentrations used were found to be of comparable overall immunogenicity with regard to Lymph Node activation and the induction of Lymph Node Cell proliferation, there were apparent differences in humoral immune responses. Thus, not only did exposure to TMA stimulate increases in total serum IgE concentration and the production of specific IgE antibody, but also a more vigorous IgG antibody response was provoked by TMA compared with DNCB. These data suggest that the measurement of induced changes in serum IgE concentration in the BN strain of rat is able to differentiate between different classes of chemical allergen. Given the inter-animal variation in IgE production, it would be prudent to incorporate a concurrent assessment of responses induced by treatment with TMA as a positive control against which to assess the activity of other test materials.
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contact allergenic potency correlation of human and local Lymph Node assay data
American Journal of Contact Dermatitis, 2001Co-Authors: Frank G Gerberick, Rebecca Jane Dearman, Cindy A Ryan, Michael K Robinson, Zoe M Wright, David A Basketter, Ian Kimber, James G. MarksAbstract:BACKGROUND: Effective toxicologic evaluation of skin sensitization requires that potential contact allergens are identified and that the likely risks of sensitization among exposed populations are assessed. By definition, chemicals that are classified as contact sensitizers have the capacity to cause allergic contact dermatitis (ACD) in humans. However, this hazard is not an all-or-nothing phenomenon; clear dose-response relationships can be discerned and thresholds identified for both the induction of sensitization and the elicitation of ACD. Commonly, these parameters are grouped under the heading of potency, the determination of which is vital for risk assessment. Preclinical testing for sensitization potential is critically important for hazard assessment before human exposure. The murine local Lymph Node assay (LLNA) is the most recently accepted test method for sensitization hazard assessment. OBJECTIVE: The aim was to compare potency estimations derived from LLNA data with clinical determinations of relative potency based on human data. METHODS: No-effect levels (NOELs) for a range of 21 chemicals were determined from nondiagnostic human repeat patch test studies as reported in the literature. These levels were compared with LLNA EC(3) values, the estimated concentration required to produce a 3-fold increase (positive response) in draining Lymph Node Cell (LNC) proliferative activity. RESULTS: Using available human repeat patch test data, together with expert judgment, the compounds were classified as strong, moderate, weak, extremely weak, or nonsensitizing. Additionally, the potency of each chemical was classified independently based on its LLNA EC(3) value. The results show clearly that LLNA EC(3) values are very comparable with the NOELs calculated from the literature. Moreover, the potency rankings based upon LLNA EC(3) data support their human classification. CONCLUSION: The present investigations show that the LLNA can be used to provide quantitative estimates of relative skin sensitizing potency EC(3) values that correlate closely with NOELs established from human repeat patch testing and from our clinical experience.
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use of the local Lymph Node assay for the estimation of relative contact allergenic potency
Contact Dermatitis, 2000Co-Authors: David A Basketter, Rebecca Jane Dearman, L Blaikie, Paul Harvey, Cindy A Ryan, Ian Kimber, G. Frank Gerberick, Ian R White, P Evans, Richard J. RycroftAbstract:The effective toxicological evaluation of skin sensitization demands that potential contact allergens are identified and that the likely risks of sensitization among exposed populations assessed. By definition, chemicals which possess the toxicological property of skin sensitization potentially are capable of causing allergic contact dermatitis (ACD) in humans. However, this hazard is not an all-or-none phenomenon; clear dose-response relationships can be discerned and thresholds identified for both the induction of sensitization and the elicitation of contact dermatitis. Commonly, these parameters are grouped under the heading of potency, determination of which is vital for risk assessment. In the present investigation, the local Lymph Node assay (LLNA) has been employed to determine the relative potency of a range of 20 chemicals. The parameter used is the estimated concentration required to produce a 3-fold increase in draining Lymph-Node Cell proliferative activity, the EC3 value. These measurements have been compared with an assessment of the human sensitizing potency of the 20 selected chemicals, each being assigned to 1 of 5 classes based on their human sensitizing potency. The EC3 value, derived from LLNA work carried out in acetone/ olive oil vehicle, correlated well with the human classification, with the strongest sensitizers having low EC3 values (
David A Basketter - One of the best experts on this subject based on the ideXlab platform.
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performance standards and alternative assays practical insights from skin sensitization
Regulatory Toxicology and Pharmacology, 2013Co-Authors: Susanne N Kolle, David A Basketter, Hanswerner Vohr, Silvia Casati, William S Stokes, Judy Strickland, Bennard Van Ravenzwaay, Robert LandsiedelAbstract:Abstract To encourage the development and validation of alternative toxicity test methods, the effort required for validation of test methods proposed for regulatory purposes should be minimized. Performance standards (PS) facilitate efficient validation by requiring limited testing. Based on the validated method, PS define accuracy and reliability values that must be met by the new similar test method. The OECD adopted internationally harmonized PS for evaluating new endpoint versions of the local Lymph Node assay (LLNA). However, in the process of evaluating a Lymph Node Cell count alternative (LNCC), simultaneous conduct of the regulatory LLNA showed that this standard test may not always perform in perfect accord with its own PS. The LNCC results were similar to the concurrent LLNA. Discrepancies between PS, LLNA and LNCC were largely associated with “borderline” substances and the variability of both endpoints. Two key lessons were learned: firstly, the understandable focus on substances close to the hazard classification borderline are more likely to emphasise issues of biological variability, which should be taken into account during the evaluation of results; secondly, variability in the results for the standard assay should be considered when selecting reference chemicals for PS.
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contact allergenic potency correlation of human and local Lymph Node assay data
American Journal of Contact Dermatitis, 2001Co-Authors: Frank G Gerberick, Rebecca Jane Dearman, Cindy A Ryan, Michael K Robinson, Zoe M Wright, David A Basketter, Ian Kimber, James G. MarksAbstract:BACKGROUND: Effective toxicologic evaluation of skin sensitization requires that potential contact allergens are identified and that the likely risks of sensitization among exposed populations are assessed. By definition, chemicals that are classified as contact sensitizers have the capacity to cause allergic contact dermatitis (ACD) in humans. However, this hazard is not an all-or-nothing phenomenon; clear dose-response relationships can be discerned and thresholds identified for both the induction of sensitization and the elicitation of ACD. Commonly, these parameters are grouped under the heading of potency, the determination of which is vital for risk assessment. Preclinical testing for sensitization potential is critically important for hazard assessment before human exposure. The murine local Lymph Node assay (LLNA) is the most recently accepted test method for sensitization hazard assessment. OBJECTIVE: The aim was to compare potency estimations derived from LLNA data with clinical determinations of relative potency based on human data. METHODS: No-effect levels (NOELs) for a range of 21 chemicals were determined from nondiagnostic human repeat patch test studies as reported in the literature. These levels were compared with LLNA EC(3) values, the estimated concentration required to produce a 3-fold increase (positive response) in draining Lymph Node Cell (LNC) proliferative activity. RESULTS: Using available human repeat patch test data, together with expert judgment, the compounds were classified as strong, moderate, weak, extremely weak, or nonsensitizing. Additionally, the potency of each chemical was classified independently based on its LLNA EC(3) value. The results show clearly that LLNA EC(3) values are very comparable with the NOELs calculated from the literature. Moreover, the potency rankings based upon LLNA EC(3) data support their human classification. CONCLUSION: The present investigations show that the LLNA can be used to provide quantitative estimates of relative skin sensitizing potency EC(3) values that correlate closely with NOELs established from human repeat patch testing and from our clinical experience.
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use of the local Lymph Node assay for the estimation of relative contact allergenic potency
Contact Dermatitis, 2000Co-Authors: David A Basketter, Rebecca Jane Dearman, L Blaikie, Paul Harvey, Cindy A Ryan, Ian Kimber, G. Frank Gerberick, Ian R White, P Evans, Richard J. RycroftAbstract:The effective toxicological evaluation of skin sensitization demands that potential contact allergens are identified and that the likely risks of sensitization among exposed populations assessed. By definition, chemicals which possess the toxicological property of skin sensitization potentially are capable of causing allergic contact dermatitis (ACD) in humans. However, this hazard is not an all-or-none phenomenon; clear dose-response relationships can be discerned and thresholds identified for both the induction of sensitization and the elicitation of contact dermatitis. Commonly, these parameters are grouped under the heading of potency, determination of which is vital for risk assessment. In the present investigation, the local Lymph Node assay (LLNA) has been employed to determine the relative potency of a range of 20 chemicals. The parameter used is the estimated concentration required to produce a 3-fold increase in draining Lymph-Node Cell proliferative activity, the EC3 value. These measurements have been compared with an assessment of the human sensitizing potency of the 20 selected chemicals, each being assigned to 1 of 5 classes based on their human sensitizing potency. The EC3 value, derived from LLNA work carried out in acetone/ olive oil vehicle, correlated well with the human classification, with the strongest sensitizers having low EC3 values (
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influence of application vehicle on skin sensitization to methylchloroisothiazolinone methylisothiazolinone an analysis using the local Lymph Node assay
Contact Dermatitis, 1999Co-Authors: E V Warbrick, David A Basketter, R J Dearman, Ian KimberAbstract:The murine local Lymph Node assay (LLNA) is a method for the identification of skin sensitizing chemicals in which activity is measured as a function of proliferative responses induced in draining Lymph Nodes following topical exposure of mice to the test material. More recently, the LLNA has also been used for the determination of relative skin sensitizing potency based upon the mathematical derivation of an EC3 value, this being the estimated concentration of test chemical necessary to provoke a 3-fold increase in Lymph-Node Cell-proliferative activity compared with concurrent vehicle-treated controls. Here we describe the use of the LLNA to determine the influence of vehicle on the skin-sensitizing potency of methylchloroisothiazolinone/methylisothiazolinone (MCI/MI), the active ingredient of preservatives such as Kathon CG. To this end, LLNA responses to MCI/ MI were measured using the vehicles 4:1 acetone:olive oil (AOO), methyl ethyl ketone, dimethylsulfoxide, dimethylformamide, propylene glycol (PG) and acetone. It was found that the vehicle in which MCI/MI was applied had a substantial impact on activity, with derived EC3 values varying from 0.0049% with AOO to 0.048% with PG. With the other vehicles, EC3 values ranged from 0.0068 to 0.0076%. The skin sensitizing potency of MCI/MI as judged from LLNA responses is consistent with what is known of the requirements for sensitization in humans. It is proposed that the LLNA not only provides a method for determination of relative skin sensitizing potency, but is also appropriate for assessing the influence of vehicle matrix on sensitizing activity.
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a comparison of statistical approaches to the derivation of ec3 values from local Lymph Node assay dose responses
Journal of Applied Toxicology, 1999Co-Authors: David A Basketter, Rebecca Jane Dearman, L J Lea, Andrea Dickens, Ian Pate, David Briggs, Ian KimberAbstract:Effective risk assessment and management of allergic contact dermatitis require three key factors: adequate hazard identification, measurement of the relative potency of identified hazards and an understanding of the nature, extent and duration of exposure. Suitable methods for hazard identification, such as the murine local Lymph Node assay (LLNA) and the guinea-pig maximization test, are well established and conditions of human exposure normally can be well anticipated. Thus, the need is for a robust and quantitative method for the estimation of relative skin sensitizing potency. One possible approach is via the analysis of LLNA dose-response data. In the LLNA, contact allergens are defined currently as those chemicals that cause a threefold or greater increase in Lymph Node Cell proliferative activity compared with concurrent vehicle-treated controls. It is possible to estimate the concentration of a sensitizer required to generate a threefold stimulation of proliferation in draining Lymph Nodes; such a concentration is known as the EC3 value. Using a variety of statistical approaches to derive EC3 values from LLNA dose-response data for 10 chemicals, it has been demonstrated that simple linear interpolation between the values either side of the threefold stimulation index provides a robust assessment of the EC3 value without the need for recourse to more sophisticated statistical techniques. Provided that the appropriate concentrations of test chemical have been selected, EC3 values obtained in this way are reproducible both within and between laboratories and form the basis for examination of the utility of this approach for the estimation of relative skin sensitizing potency.
L J Lea - One of the best experts on this subject based on the ideXlab platform.
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potency values from the local Lymph Node assay application to classification labelling and risk assessment
Regulatory Toxicology and Pharmacology, 2010Co-Authors: Scott E Loveless, Ian R. Jowsey, Petra Kern, A Gamer, L J Lea, Eric Debruyne, Ian Kimber, Anne Marie Api, Rene W R Crevel, P LloydAbstract:Abstract Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local Lymph Node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: ‘extreme’, ‘strong’, ‘moderate’ and ‘weak’. Since draining Lymph Node Cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.
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potency values from the local Lymph Node assay application to classification labelling and risk assessment
Regulatory Toxicology and Pharmacology, 2010Co-Authors: Scott E Loveless, Ian R. Jowsey, Petra Kern, A Gamer, L J Lea, Eric Debruyne, Ian Kimber, Anne Marie Api, Rene W R Crevel, P LloydAbstract:Abstract Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local Lymph Node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: ‘extreme’, ‘strong’, ‘moderate’ and ‘weak’. Since draining Lymph Node Cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.
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local Lymph Node assay validation assessment for regulatory purposes
American Journal of Contact Dermatitis, 2000Co-Authors: G. Frank Gerberick, Rebecca Jane Dearman, Cindy A Ryan, Ian Kimber, L J LeaAbstract:For the prediction of skin sensitization potential of substances, the murine local Lymph Node assay (LLNA) is an alternative to the widely used guinea pig tests. For more than 10 years, this method has undergone extensive development, evaluation, and validation. In this review, the validation status of the LLNA is considered, specifically with regard to its use for regulatory identification of skin sensitization hazards. The LLNA is a method for the predictive identification of chemicals that have a potential to cause skin sensitization. Activity is measured as a function of Lymph Node Cell proliferative responses stimulated by topical application of test chemicals. The LLNA has successfully passed all reasonable validation stages. It provides a reliable and relevant source of predictive skin sensitization data, which unlike results from guinea pig tests, are reproducible from laboratory to laboratory. In summary, the LLNA is now ready for acceptance as a viable and complete alternative to traditional methods, offering a substantial reduction in animal numbers and refinement opportunities without compromising the standards for the identification of important skin sensitizers.
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a comparison of statistical approaches to the derivation of ec3 values from local Lymph Node assay dose responses
Journal of Applied Toxicology, 1999Co-Authors: David A Basketter, Rebecca Jane Dearman, L J Lea, Andrea Dickens, Ian Pate, David Briggs, Ian KimberAbstract:Effective risk assessment and management of allergic contact dermatitis require three key factors: adequate hazard identification, measurement of the relative potency of identified hazards and an understanding of the nature, extent and duration of exposure. Suitable methods for hazard identification, such as the murine local Lymph Node assay (LLNA) and the guinea-pig maximization test, are well established and conditions of human exposure normally can be well anticipated. Thus, the need is for a robust and quantitative method for the estimation of relative skin sensitizing potency. One possible approach is via the analysis of LLNA dose-response data. In the LLNA, contact allergens are defined currently as those chemicals that cause a threefold or greater increase in Lymph Node Cell proliferative activity compared with concurrent vehicle-treated controls. It is possible to estimate the concentration of a sensitizer required to generate a threefold stimulation of proliferation in draining Lymph Nodes; such a concentration is known as the EC3 value. Using a variety of statistical approaches to derive EC3 values from LLNA dose-response data for 10 chemicals, it has been demonstrated that simple linear interpolation between the values either side of the threefold stimulation index provides a robust assessment of the EC3 value without the need for recourse to more sophisticated statistical techniques. Provided that the appropriate concentrations of test chemical have been selected, EC3 values obtained in this way are reproducible both within and between laboratories and form the basis for examination of the utility of this approach for the estimation of relative skin sensitizing potency.
P Lloyd - One of the best experts on this subject based on the ideXlab platform.
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potency values from the local Lymph Node assay application to classification labelling and risk assessment
Regulatory Toxicology and Pharmacology, 2010Co-Authors: Scott E Loveless, Ian R. Jowsey, Petra Kern, A Gamer, L J Lea, Eric Debruyne, Ian Kimber, Anne Marie Api, Rene W R Crevel, P LloydAbstract:Abstract Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local Lymph Node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: ‘extreme’, ‘strong’, ‘moderate’ and ‘weak’. Since draining Lymph Node Cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.
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potency values from the local Lymph Node assay application to classification labelling and risk assessment
Regulatory Toxicology and Pharmacology, 2010Co-Authors: Scott E Loveless, Ian R. Jowsey, Petra Kern, A Gamer, L J Lea, Eric Debruyne, Ian Kimber, Anne Marie Api, Rene W R Crevel, P LloydAbstract:Abstract Hundreds of chemicals are contact allergens but there remains a need to identify and characterise accurately skin sensitising hazards. The purpose of this review was fourfold. First, when using the local Lymph Node assay (LLNA), consider whether an exposure concentration (EC3 value) lower than 100% can be defined and used as a threshold criterion for classification and labelling. Second, is there any reason to revise the recommendation of a previous ECETOC Task Force regarding specific EC3 values used for sub-categorisation of substances based upon potency? Third, what recommendations can be made regarding classification and labelling of preparations under GHS? Finally, consider how to integrate LLNA data into risk assessment and provide a rationale for using concentration responses and corresponding no-effect concentrations. Although skin sensitising chemicals having high EC3 values may represent only relatively low risks to humans, it is not possible currently to define an EC3 value below 100% that would serve as an appropriate threshold for classification and labelling. The conclusion drawn from reviewing the use of distinct categories for characterising contact allergens was that the most appropriate, science-based classification of contact allergens according to potency is one in which four sub-categories are identified: ‘extreme’, ‘strong’, ‘moderate’ and ‘weak’. Since draining Lymph Node Cell proliferation is related causally and quantitatively to potency, LLNA EC3 values are recommended for determination of a no expected sensitisation induction level that represents the first step in quantitative risk assessment.
Rebecca Jane Dearman - One of the best experts on this subject based on the ideXlab platform.
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contact allergenic potency correlation of human and local Lymph Node assay data
American Journal of Contact Dermatitis, 2001Co-Authors: Frank G Gerberick, Rebecca Jane Dearman, Cindy A Ryan, Michael K Robinson, Zoe M Wright, David A Basketter, Ian Kimber, James G. MarksAbstract:BACKGROUND: Effective toxicologic evaluation of skin sensitization requires that potential contact allergens are identified and that the likely risks of sensitization among exposed populations are assessed. By definition, chemicals that are classified as contact sensitizers have the capacity to cause allergic contact dermatitis (ACD) in humans. However, this hazard is not an all-or-nothing phenomenon; clear dose-response relationships can be discerned and thresholds identified for both the induction of sensitization and the elicitation of ACD. Commonly, these parameters are grouped under the heading of potency, the determination of which is vital for risk assessment. Preclinical testing for sensitization potential is critically important for hazard assessment before human exposure. The murine local Lymph Node assay (LLNA) is the most recently accepted test method for sensitization hazard assessment. OBJECTIVE: The aim was to compare potency estimations derived from LLNA data with clinical determinations of relative potency based on human data. METHODS: No-effect levels (NOELs) for a range of 21 chemicals were determined from nondiagnostic human repeat patch test studies as reported in the literature. These levels were compared with LLNA EC(3) values, the estimated concentration required to produce a 3-fold increase (positive response) in draining Lymph Node Cell (LNC) proliferative activity. RESULTS: Using available human repeat patch test data, together with expert judgment, the compounds were classified as strong, moderate, weak, extremely weak, or nonsensitizing. Additionally, the potency of each chemical was classified independently based on its LLNA EC(3) value. The results show clearly that LLNA EC(3) values are very comparable with the NOELs calculated from the literature. Moreover, the potency rankings based upon LLNA EC(3) data support their human classification. CONCLUSION: The present investigations show that the LLNA can be used to provide quantitative estimates of relative skin sensitizing potency EC(3) values that correlate closely with NOELs established from human repeat patch testing and from our clinical experience.
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use of the local Lymph Node assay for the estimation of relative contact allergenic potency
Contact Dermatitis, 2000Co-Authors: David A Basketter, Rebecca Jane Dearman, L Blaikie, Paul Harvey, Cindy A Ryan, Ian Kimber, G. Frank Gerberick, Ian R White, P Evans, Richard J. RycroftAbstract:The effective toxicological evaluation of skin sensitization demands that potential contact allergens are identified and that the likely risks of sensitization among exposed populations assessed. By definition, chemicals which possess the toxicological property of skin sensitization potentially are capable of causing allergic contact dermatitis (ACD) in humans. However, this hazard is not an all-or-none phenomenon; clear dose-response relationships can be discerned and thresholds identified for both the induction of sensitization and the elicitation of contact dermatitis. Commonly, these parameters are grouped under the heading of potency, determination of which is vital for risk assessment. In the present investigation, the local Lymph Node assay (LLNA) has been employed to determine the relative potency of a range of 20 chemicals. The parameter used is the estimated concentration required to produce a 3-fold increase in draining Lymph-Node Cell proliferative activity, the EC3 value. These measurements have been compared with an assessment of the human sensitizing potency of the 20 selected chemicals, each being assigned to 1 of 5 classes based on their human sensitizing potency. The EC3 value, derived from LLNA work carried out in acetone/ olive oil vehicle, correlated well with the human classification, with the strongest sensitizers having low EC3 values (
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local Lymph Node assay validation assessment for regulatory purposes
American Journal of Contact Dermatitis, 2000Co-Authors: G. Frank Gerberick, Rebecca Jane Dearman, Cindy A Ryan, Ian Kimber, L J LeaAbstract:For the prediction of skin sensitization potential of substances, the murine local Lymph Node assay (LLNA) is an alternative to the widely used guinea pig tests. For more than 10 years, this method has undergone extensive development, evaluation, and validation. In this review, the validation status of the LLNA is considered, specifically with regard to its use for regulatory identification of skin sensitization hazards. The LLNA is a method for the predictive identification of chemicals that have a potential to cause skin sensitization. Activity is measured as a function of Lymph Node Cell proliferative responses stimulated by topical application of test chemicals. The LLNA has successfully passed all reasonable validation stages. It provides a reliable and relevant source of predictive skin sensitization data, which unlike results from guinea pig tests, are reproducible from laboratory to laboratory. In summary, the LLNA is now ready for acceptance as a viable and complete alternative to traditional methods, offering a substantial reduction in animal numbers and refinement opportunities without compromising the standards for the identification of important skin sensitizers.
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a comparison of statistical approaches to the derivation of ec3 values from local Lymph Node assay dose responses
Journal of Applied Toxicology, 1999Co-Authors: David A Basketter, Rebecca Jane Dearman, L J Lea, Andrea Dickens, Ian Pate, David Briggs, Ian KimberAbstract:Effective risk assessment and management of allergic contact dermatitis require three key factors: adequate hazard identification, measurement of the relative potency of identified hazards and an understanding of the nature, extent and duration of exposure. Suitable methods for hazard identification, such as the murine local Lymph Node assay (LLNA) and the guinea-pig maximization test, are well established and conditions of human exposure normally can be well anticipated. Thus, the need is for a robust and quantitative method for the estimation of relative skin sensitizing potency. One possible approach is via the analysis of LLNA dose-response data. In the LLNA, contact allergens are defined currently as those chemicals that cause a threefold or greater increase in Lymph Node Cell proliferative activity compared with concurrent vehicle-treated controls. It is possible to estimate the concentration of a sensitizer required to generate a threefold stimulation of proliferation in draining Lymph Nodes; such a concentration is known as the EC3 value. Using a variety of statistical approaches to derive EC3 values from LLNA dose-response data for 10 chemicals, it has been demonstrated that simple linear interpolation between the values either side of the threefold stimulation index provides a robust assessment of the EC3 value without the need for recourse to more sophisticated statistical techniques. Provided that the appropriate concentrations of test chemical have been selected, EC3 values obtained in this way are reproducible both within and between laboratories and form the basis for examination of the utility of this approach for the estimation of relative skin sensitizing potency.
