PMID- 17703503
OWN - NLM
STAT- MEDLINE
DCOM- 20080715
LR  - 20101118
IS  - 0260-437X (Print)
IS  - 0260-437X (Linking)
VI  - 28
IP  - 4
DP  - 2008 May
TI  - Chemical reactivity indices and mechanism-based read-across for non-animal based 
      assessment of skin sensitisation potential.
PG  - 443-54
AB  - The skin sensitisation potential of chemicals is currently assessed using in vivo 
      methods where the murine local lymph node assay (LLNA) is typically the method of 
      first choice. Current regulatory initiatives are driving the impetus for the use 
      of in vitro/in silico alternative approaches to provide the relevant information 
      needed for the effective assessment of skin sensitisation, for both hazard 
      characterisation and risk assessment purposes. A chemical must undergo a number 
      of steps for it to induce skin sensitisation but the main determining step is 
      formation of a stable covalent association with carrier protein. The ability of a 
      chemical to react covalently with carrier protein nucleophiles relates to both 
      its electrophilic reactivity and its hydrophobicity. This paper focuses on 
      quantitative indices of electrophilic reactivity with nucleophiles, in a chemical 
      mechanism-of-action context, and compares and contrasts the experimental 
      approaches available to generate reactivity data that are suitable for 
      mathematical modelling and making predictions of skin sensitisation potential, 
      using new chemistry data correlated against existing in vivo bioassay data. As 
      such, the paper goes on to describe an illustrative example of how quantitative 
      kinetic measures of reactivity can be usefully and simply applied to perform 
      mechanism-based read-across that enables hazard characterisation of skin 
      sensitisation potential. An illustration of the types of quantitative mechanistic 
      models that could be built using databases of kinetic measures of reactivity, 
      hydrophobicity and existing in vivo bioassay data is also given.
CI  - Copyright (c) 2007 John Wiley & Sons, Ltd.
FAU - Roberts, David W
AU  - Roberts DW
AD  - School of Pharmacy and Chemistry, Liverpool John Moores University, England. 
      d.w.roberts@ljmu.ac.uk <d.w.roberts@ljmu.ac.uk>
FAU - Aptula, Aynur O
AU  - Aptula AO
FAU - Patlewicz, Grace
AU  - Patlewicz G
FAU - Pease, Camilla
AU  - Pease C
LA  - eng
PT  - Journal Article
PT  - Review
PL  - England
TA  - J Appl Toxicol
JT  - Journal of applied toxicology : JAT
JID - 8109495
RN  - 0 (Irritants)
SB  - IM
MH  - *Animal Testing Alternatives
MH  - Animals
MH  - Biological Assay
MH  - Cells, Cultured
MH  - Databases, Factual
MH  - Humans
MH  - Hydrophobic and Hydrophilic Interactions
MH  - Irritants/chemistry/metabolism/*toxicity
MH  - Kinetics
MH  - Local Lymph Node Assay
MH  - Mice
MH  - *Models, Biological
MH  - *Models, Chemical
MH  - Molecular Structure
MH  - Protein Binding
MH  - Quantitative Structure-Activity Relationship
MH  - *Risk Assessment
MH  - *Skin Irritancy Tests
RF  - 62
EDAT- 2007/08/19 09:00
MHDA- 2008/07/17 09:00
CRDT- 2007/08/19 09:00
PHST- 2007/08/19 09:00 [pubmed]
PHST- 2008/07/17 09:00 [medline]
PHST- 2007/08/19 09:00 [entrez]
AID - 10.1002/jat.1293 [doi]
PST - ppublish
SO  - J Appl Toxicol. 2008 May;28(4):443-54. doi: 10.1002/jat.1293.