Research Topic task started on Mon Jul 21, 2003 at 2:15 PM

3 Research Topic candidates were identified in CAPLUS and MEDLINE.

using the phrase " quantitative structure-activity relationship local lymph node assay"

Selected 1 of 3 candidate topics.

14 references were found containing both of the concepts "quantitative structure-activity local" and "lymph
node assay".

Copyrights:

Copyright 2003 ACS (The UK patent material in this product/service is UK Crown copyright and is made available
with permission. (C) Crown Copyright.    The French (FR) patent material
in this product/service is made available from Institut National de la
Propriete Industrielle (INPI).)    for database CAPLUS
Produced by the U.S. National Library of Medicine for database MEDLINE
Copyright 2003 ACS (Some records contain information from GenBank(R). See also: Benson D.A., Karsch-
Mizrachi I., Lipman D.J., Ostell J., Rapp B.A., Wheeler D.L. Genbank.
Nucl. Acids Res. 28(1):15-18 (2000). Property values tagged with IC are
from the ZIC/VINITI data file provided by InfoChem.) for database
REGISTRY
Copyright 2003 ACS (Some records from 1974 to 1991 are derived from the ZIC/VINITI data file provided by
InfoChem. Some records are produced using some INPI data from the
period prior to 1986.) for database CASREACT
Copyright 2003    ACS for databases CHEMCATS and CHEMLIST

Bibliographic Information

Structure-activity relationships for selected fragrance allergens.        Patlewicz, G. Y.; Wright, Z. M.; Basketter,
D. A.; Pease, C. K.; Lepoittevin, J.-P.; Arnau, E. Gimenez.        Unilever Research & Development,    Safety and
Environmental Assurance Centre,    Bedford,    UK.        Contact Dermatitis    (2002),    47(4),    219-226.    CODEN:
CODEDG    ISSN: 0105-1873.    Journal    written in English.        AN 2003:82005        CAPLUS      (Copyright 2003
ACS)   

Abstract

Fragrance substances represent a very diverse group of chems., a proportion of them providing not only desirable
aroma characteristics, but also being assocd. with adverse effects, notably the ability to cause allergic reactions in
the skin.    However, efforts to find substitute materials are hampered by the need to undertake animal testing to
evaluate both the presence and the degree of skin sensitization hazard.    One potential route to avoid such testing is
to understand the relationships between chem. structure and skin sensitization.    In the present work the authors have
evaluated two groups of fragrance chems., satd. aldehydes (aryl substituted and aliph. aldehydes) and ,-unsatd.
aldehydes.    Data on their skin sensitization potency defined using the local lymph node assay has been evaluated in
relation to their physicochem. properties.    The initial outcome has been consistent with the concept that ,-unsatd.
aldehydes react largely via Michael addn., while the group of satd. aldehydes form Schiff bases with proteins.   
Simple models of chem. reactivity based on these mechanisms suggest that it may be possible to predict allergenic
potency.    Accordingly, the evaluation of an addnl. group of similar aldehydes is now underway to assess the
robustness of these models, with some emphasis being based on ensuring a wider spread of chem. reactivity.

Bibliographic Information

Quantitative structure-activity relationships: sulfonate esters in the local lymph node assay.        Roberts, D.
W.; Basketter, D. A.        Unilever Research,    Bebington, Wirral,    UK.        Contact Dermatitis    (2000),    42(3),   
154-161.    CODEN: CODEDG    ISSN: 0105-1873.    Journal    written in English.        CAN 133:27461        AN
2000:168248        CAPLUS      (Copyright 2003 ACS)   

Abstract

The biol. activity of skin-sensitizing chems. is related to their ability to react, either directly or after metabolic
activation, with appropriate skin proteins.    For direct acting electrophilic compds., this ability can be modeled,
using the RAI (relative alkylation index) approach, by a combination of electrophilicity and hydrophobicity
parameters.    The development of predictive quant. structure-activity relationships (QSAR) models of skin
sensitization, using mechanism-based physicochem. parameters, has been greatly facilitated by the introduction of
the murine local lymph node assay (LLNA), which is able to describe the extent of the biol. response in objective
and quant. terms.    In the present work, sensitization response data in the LLNA is generated for a series of 6
sulfonate esters.    An RAI-based hybrid QSAR/dose-response relationship is derived using a neg. hydrophobicity
coeff. in the RAI expression, to model the effect of retention of the hydrophobic test chems. in the stratum corneum. 
Dose-response analyses are used to est. EC3 and EC20 values as quant. indexes of skin sensitization potential for
each compd., and regression anal. is applied to develop QSARs correlating these EC3 and EC20 values with an
RAI-based parameter.    The high statistical quality of these QSARs demonstrates both the consistency of the LLNA
method for generating high quality skin sensitization data, and the value of the RAI approach in development of
math. models for skin sensitization.

Bibliographic Information

Alternative to animal testing of skin sensitization.        Yamazaki, Shunsuke.        Cosmet. Lab.,    Kanebo Ltd.,   
Odawara,    Japan.        Fragrance Journal    (1999),    27(7),    56-63.    CODEN: FUJAD7    ISSN: 0288-9803.   
Journal; General Review    written in Japanese.        CAN 131:154526        AN 1999:482212        CAPLUS     
(Copyright 2003 ACS)   

Abstract

A review with 47 refs., on the mechanisms of skin sensitization and allergic contact dermatitis, animal expts. for
skin sensitization (guinea pig maximization test, Buehler test, mouse ear swelling test, and local lymph node assay),
and alternative methods (protein-binding assay, use of human blood-derived dendritic cells, QSAR, and repeat insult
patch test).    Evaluation of skin sensitization of chems. by detn. of mRNA for cytokines is also discussed.

Bibliographic Information

Structure-activity relationships in the murine local lymph node assay for skin sensitization: ,-diketones.       
Roberts, D. W.; York, M.; Basketter, D. A.        Unilever Research Port Sunlight,    Merseyside,    UK.        Contact
Dermatitis    (1999),    41(1),    14-17.    CODEN: CODEDG    ISSN: 0105-1873.    Journal    written in English.       
CAN 131:253454        AN 1999:442087        CAPLUS      (Copyright 2003 ACS)   

Abstract

The biol. activity of skin-sensitizing chems. is related to their ability to react, either directly or after metabolic
activation, with appropriate skin proteins.    For direct acting electrophilic compds., this ability can be modeled,
using the RAI (relative alkylation index) approach, by a combination of electrophilicity and hydrophobicity
parameters.    Several structure-activity relationships based on this approach have been reported, but most of them
cover guinea pig sensitization test data on what chemists would classify as relatively soft electrophilic chems.    In
the present work, an electrophilicity parameter based on Taft substituent consts. is derived for hard electrophiles
having a reactive carbonyl group, and is used to calc. RAI values for the anal. of sensitization test data obtained in
the murine local lymph node assay (LLNA) for a series of ,-diketones.    The sensitization potential of these
reactive hard electrophilic carbonyl compds. in the LLNA shows a good correlation with the RAI.    Overall, the
findings reaffirm our view that phys. org. chem. is the key to understanding why some chems. sensitize more
strongly than others, while some do not sensitize at all, and provide further evidence of the value of the LLNA for
SAR studies.
Bibliographic Information

Structure activity relationships in skin sensitization using the murine local lymph node assay.        Ashby, J.;
Basketter, D. A.; Paton, D.; Kimber, I.        Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield,   
Cheshire,    UK.        Toxicology    (1995),    103(3),    177-94.    CODEN: TXCYAC    ISSN: 0300-483X.    Journal   
written in English.        CAN 124:78944        AN 1996:7610        CAPLUS      (Copyright 2003 ACS)   

Abstract

Murine local lymph assay node data for 106 chems. are listed.    Among these, 73 are active in the assay indicating
their potential as skin sensitizing agents.    Broad structure activity relationships (SAR) are suggested based on the
electrophilic theory of skin sensitization suggested by Landsteiner and Jacobs in 1936, and elaborated by Dupuis and
Benezra in 1982.    Eight classes of agent are discerned; electrophiles, potential electrophiles after metab., Michael-
reactive agents, benzoylating agents, ionic chems. and misc. agents.    The electrophilic theory cannot at present fully
explain the activity of agents in the last two classes.    That fact will hopefully focus research into their mode of
action.    Some chems. fit equally into more than one class, and such agents are entered into the several classes in
order not to bias the anal.    Attention is given to why not all chems. of a class are active in the assay.    It is
concluded that a combination of inappropriate lipophilicity, mol. size and metabolic detoxification are responsible
for these inactivities.    Given a sufficient no. of analogs tested within each class it should be possible eventually to
predict with accuracy the skin sensitizing potential of new members of the class.    However, the present anal. is
qual., not quant.    Finally, the parallelism between sensitizing potential and mutagenic potential for chems. is
explored further.

Bibliographic Information

A local lymph-node assay validation study of a structure-activity relationship model for contact allergens.       
Hostynek, J. J.; Lauerma, A. I.; Magee, P. S.; Bloom, E.; Maibach, H. I.        Dep. Dermatol.,    Univ. California,    San
Francisco,    CA,    USA.        Archives of Dermatological Research    (1995),    287(6),    567-71.    CODEN: ADREDL 
ISSN: 0340-3696.    Journal    written in English.        CAN 123:162836        AN 1995:752579        CAPLUS     
(Copyright 2003 ACS)   

Abstract

A structure-activity relation model for prediction of contact allergenic potential of chems. had previously been
developed.    The model had been shown to be able to classify known allergens and non-allergens using data on
physicochem. and reactivity parameters of functional groups by discriminant two-value multiple regression anal.   
To investigate the model, six selected chems. which had not been previously investigated for allergenicity were
studied with both the model and a murine local lymph node assay.    The same compds. were predicted to the
allergens (3-bromo-2-coumaranone, 1-nitrocyclohexene and -acryloyloxy-, -dimethyl--butyrolactone) and non-
allergens (1-carbethoxy-4-piperidone, 6,7-dimethoxy-2-tetralone and 9-acetylanthracene) by both the model and the
local lymph-node assay.

Bibliographic Information

The value of the local lymph node assay in the development of QSARs for skin sensitization potential.       
Basketter, David A.; Roberts, David; Cronin, Mark T. D.; Scholes, Eddie.        Unilever Environ. Saf. Lab.,   
Sharnbrook,    UK.    Editor(s): Wermuth, Camille-Georges.        Trends QSAR Mol. Modell. 92, Proc. Eur. Symp.
Struct.-Act. Relat.:    QSAR Mol. Modell., 9th    (1993),    Meeting Date 1992,          580-3.    Publisher: ESCOM,   
Leiden, Neth    CODEN: 59XTAS    Conference    written in English.        CAN 121:75433        AN 1994:475433       
CAPLUS      (Copyright 2003 ACS)   

Abstract

The ability of the local lymph node assay to yield valid and reproducible data susceptible to quant. structure-activity
relationship (QSAR) anal. for the assessment of skin sensitizing potential is demonstrated utilizing a range of
haloalkanes.

Bibliographic Information

The value of the local lymph node assay in quantitative structure-activity investigations.        Basketter, D. A.;
Roberts, D. W.; Cronin, M.; Scholes, E. W.        Unilever Environ. Saf. Lab.,    Sharnbrook/Beds,    UK.        Contact
Dermatitis    (1992),    27(3),    137-42.    CODEN: CODEDG    ISSN: 0105-1873.    Journal    written in English.       
CAN 118:2127        AN 1993:2127        CAPLUS      (Copyright 2003 ACS)   

Abstract

The development of quant. correlations between the physicochem. properties of a compd. and its ability to act as a
skin sensitizer is complicated by the no. of variables assocd. with the current sensitization test data, combined with
the absence of a truly objective end point.    Recently, however, a novel approach to the assessment of skin
sensitization potential, the local lymph node assay (LLNA), has been described, which dets. the skin sensitization by
measuring lymphocyte proliferation in lymph nodes draining the site of chem. exposure.    The assay offers several
advantages over traditional methods in the context of quant. structure-activity relationship studies.    In the present
work, a range of bromoalkanes has been employed which demonstrate the robustness and reproducibility of the
LLNA.    Sensitizing activity increased with chain length up to a max. at C15/C16, whereafter the response declined. 
The data were modelled against hydrophobicity, expressed as Clog P and (ClogP)2 to fit the biphasic nature of the
results.    The results demonstrate the utility of LLNA data for interpretation in the context of quant. structure-
activity relationships, the limited no. of variables, inter-test reproducibility and quant. end point, lending themselves
to math. interpretations.

Bibliographic Information

A skin sensitization risk assessment approach for evaluation of new ingredients and products.          Gerberick G
F; Robinson M K        Procter & Gamble Company, Miami Valley Laboratory, Cincinnati, OH 45253-8707, USA.   
gerberick.gf@pg.com        AMERICAN JOURNAL OF CONTACT DERMATITIS    (2000 Jun),    11(2),    65-73.   
Journal code: 9100472.    ISSN:1046-199X.    Journal; Article; (JOURNAL ARTICLE); General Review;
(REVIEW); (REVIEW, TUTORIAL)    written in English.        DN 20363465 PubMed ID 10908173 AN 2001020022
MEDLINE (Copyright 2003 U.S. National Library of Medicine)

Abstract

Skin sensitization risk assessment of new ingredients or products is critical before their introduction into the
marketplace.    The risk assessment process described in this article involves evaluation of skin sensitization hazard,
consideration of all potential human exposures, comparative ingredient/product benchmarking, and, when
appropriate, the management of the risk.    In this article, a risk assessment process is reviewed along with a
description of the risk assessment tools that are employed for evaluating a new ingredient or product.    The basic
process we use for evaluating the skin sensitization risk of a new product or ingredient is considered a no
effect/safety factor approach.    The tools used for conducting a risk assessment include structure activity relationship
analysis, exposure assessment, preclinical testing (e.g., local lymph node assay [LNNA]) and clinical testing (e.g.,
human repeat insult patch testing [HRIPT]).    The skin sensitization risk assessment process described in this paper
has been used successfully for many years for the safe introduction of new products into the marketplace.    This
process is dynamic--it can be applied to a diversity of product categories (e.g., shampoo, transdermal drug).    In
summary, the skin sensitization risk assessment process described in this article allows one to carefully assess the
skin sensitization potential of a new ingredient or product so that it can be safely introduced into the marketplace.

Bibliographic Information

Quantitative structure-activity relationships: sulfonate esters in the local lymph node assay.          Roberts D W;
Basketter D A        Unilever Research, Port Sunlight, Bebington, Wirral, UK            CONTACT DERMATITIS    (2000
Mar),    42(3),    154-61.    Journal code: 7604950.    ISSN:0105-1873.    Journal; Article; (JOURNAL ARTICLE)   
written in English.        DN 20189700 PubMed ID 10727166 AN 2000189700        MEDLINE (Copyright 2003 U.S.
National Library of Medicine)
Abstract

The biological activity of skin-sensitizing chemicals is related to their ability to react, either directly or after
metabolic activation, with appropriate skin proteins.    For direct acting electrophilic compounds, this ability can be
modelled, using the RAI (relative alkylation index) approach, by a combination of electrophilicity and
hydrophobicity parameters.    The development of predictive quantitative structure-activity relationships (QSAR)
models of skin sensitization, using mechanism-based physicochemical parameters, has been greatly facilitated by the
introduction of the murine local lymph node assay (LLNA), which is able to describe the extent of the biological
response in objective and quantitative terms.    In the present work, sensitization response data in the LLNA is
generated for a series of 6 sulfonate esters.    An RAI-based hybrid QSAR/dose-response relationship is derived
using a negative hydrophobicity coefficient in the RAI expression, to model the effect of retention of the
hydrophobic test chemicals in the stratum corneum.    Dose-response analyses are used to estimate EC3 and EC20
values as quantitative indices of skin sensitization potential for each compound, and regression analysis is applied to
develop QSARs correlating these EC3 and EC20 values with an RAI-based parameter.    The high statistical quality
of these QSARs demonstrates both the consistency of the LLNA method for generating high quality skin
sensitization data, and the value of the RAI approach in development of mathematical models for skin sensitization.

Bibliographic Information

Structure-activity relationships in the murine local lymph node assay for skin sensitization: alpha,beta-
diketones.          Roberts D W; York M; Basketter D A        Unilever Research Port Sunlight, Wirral, Merseyside, UK   
CONTACT DERMATITIS    (1999 Jul),    41(1),    14-7.    Journal code: 7604950.    ISSN:0105-1873.    Journal;
Article; (JOURNAL ARTICLE)    written in English.        DN 99343091 PubMed ID 10416702 AN 1999343091       
MEDLINE (Copyright 2003 U.S. National Library of Medicine)

Abstract

The biological activity of skin-sensitizing chemicals is related to their ability to react, either directly or after
metabolic activation, with appropriate skin proteins.    For direct acting electrophilic compounds, this ability can be
modelled, using the RAI (relative alkylation index) approach, by a combination of electrophilicity and
hydrophobicity parameters.    Several structure-activity relationships based on this approach have been reported, but
most of them cover guinea pig sensitization test data on what chemists would classify as relatively soft electrophilic
chemicals.    In the present work, an electrophilicity parameter based on Taft substituent constants is derived for hard
electrophiles having a reactive carbonyl group, and is used to calculate RAI values for the analysis of sensitization
test data obtained in the murine local lymph node assay (LLNA) for a series of alpha, beta-diketones.    The
sensitization potential of these reactive hard electrophilic carbonyl compounds in the LLNA shows a good
correlation with the RAI.    Overall, the findings reaffirm our view that physical organic chemistry is the key to
understanding why some chemicals sensitize more strongly than others, while some do not sensitize at all, and
provide further evidence of the value of the LLNA for SAR studies.

Bibliographic Information

Structure activity relationships in skin sensitization using the murine local lymph node assay.          Ashby J;
Basketter D A; Paton D; Kimber I        Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire,
UK            TOXICOLOGY    (1995 Dec 10),    103(3),    177-94.    Journal code: 0361055.    ISSN:0300-483X.   
Journal; Article; (JOURNAL ARTICLE)    written in English.        DN 96135339 PubMed ID 8553361 AN 96135339 
MEDLINE (Copyright 2003 U.S. National Library of Medicine)

Abstract

Murine local lymph assay node data for 106 chemicals are listed.    Among these, 73 are active in the assay
indicating their potential as skin sensitizing agents.    Broad structure activity relationships (SAR) are suggested
based on the electrophilic theory of skin sensitization suggested by Landsteiner and Jacobs in 1936, and elaborated
by Dupuis and Benezra in 1982.    Eight classes of agent are discerned; electrophiles, potential electrophiles after
metabolism, Michael-reactive agents, benzoylating agents, ionic chemicals and miscellaneous agents.    The
electrophilic theory cannot at present fully explain the activity of agents in the last two classes.    That fact will
hopefully focus research into their mode of action.    Some chemicals fit equally into more than one class, and such
agents are entered into the several classes in order not to bias the analysis.    Attention is given to why not all
chemicals of a class are active in the assay.    It is concluded that a combination of inappropriate lipophilicity,
molecular size and metabolic detoxification are responsible for these inactivities.    Given a sufficient number of
analogues tested within each class it should be possible eventually to predict with accuracy the skin sensitizing
potential of new members of the class.    However, the present analysis is qualitative, not quantitative.    Finally, the
parallelism between sensitizing potential and mutagenic potential for chemicals is explored further.

Bibliographic Information

A local lymph-node assay validation study of a structure-activity relationship model for contact allergens.         
Erratum in: Arch Dermatol Res 1995;287(8):767        Hostynek J J; Lauerma A I; Magee P S; Bloom E; Maibach H I 
Department of Dermatology, University of California, San Francisco 94143-0989, USA            ARCHIVES OF
DERMATOLOGICAL RESEARCH    (1995),    287(6),    567-71.    Journal code: 8000462.    ISSN:0340-3696.   
Journal; Article; (JOURNAL ARTICLE)    written in English.        DN 96066112 PubMed ID 7487144 AN 96066112 
MEDLINE (Copyright 2003 U.S. National Library of Medicine)

Abstract

A structure-activity relationship model for prediction of contact allergenic potential of chemicals had previously
been developed.    The model had been shown to be able to classify known allergens and nonallergens using data on
physicochemical and reactivity parameters of functional groups by discriminant two-value multiple regression
analysis.    To investigate the model, six selected chemicals which had not been previously investigated for
allergenicity were studied with both the model and a murine local lymph-node assay.    The same compounds were
predicted to be allergens (3-bromo-2-coumaranone, 1-nitrocyclohexene and alpha-acryloyloxy-beta, beta-dimethyl-
beta-butyrolactone) and nonallergens (1-carbethoxy-4-piperidone, 6,7-dimethoxy-2-tetralone and 9-
acetylanthracene) by both the model and the local lymph-node assay.

Bibliographic Information

The value of the local lymph node assay in quantitative structure-activity investigations.          Basketter D A;
Roberts D W; Cronin M; Scholes E W        Unilever Environmental Safety Laboratory, Sharnbrook, Beds, UK           
CONTACT DERMATITIS    (1992 Sep),    27(3),    137-42.    Journal code: 7604950.    ISSN:0105-1873.    Journal;
Article; (JOURNAL ARTICLE)    written in English.        DN 93083166 PubMed ID 1451456 AN 93083166       
MEDLINE (Copyright 2003 U.S. National Library of Medicine)

Abstract

The development of quantitative correlations between the physicochemical properties of a compound and its ability
to act as a skin sensitizer is complicated by the number of variables associated with the current sensitization test
data, combined with the absence of a truly objective end point.    Recently, however, a novel approach to the
assessment of skin sensitization potential, the local lymph node assay (LLNA), has been described, which
determines the skin sensitization by measuring lymphocyte proliferation in lymph nodes draining the site of
chemical exposure.    The assay offers several advantages over traditional methods in the context of quantitative
structure-activity relationship studies.    In the present work, a range of bromoalkanes has been employed which
demonstrate the robustness and reproducibility of the LLNA.    Sensitizing activity increased with chain length up to
a maximum at C15/C16, whereafter the response declined.    The data were modelled against hydrophobicity,
expressed as Clog P and (ClogP)2 to fit the biphasic nature of the results.    The results demonstrate the utility of
LLNA data for interpretation in the context of quantitative structure-activity relationships, the limited number of
variables, inter-test reproducibility and quantitative end point, lending themselves to mathematical interpretations.