Predictive testing for contact allergy : comparison of some guinea pig and mouse protocols including dose-response designs
Author: Wahlkvist, Helen
Date: 2000-01-14
Location: Hudklinikens föreläsningssal, ingång B2, Karolinska sjukhuset
Time: 9.00
Department: Institutionen för medicin / Department of Medicine
Abstract
Contact allergy (delayed hypersensitivity) may develop as a result of
skin exposure to contact allergens (haptens) and can lead to allergic
contact dermatitis. The purpose of this study was to evaluate some
predictive animal test methods for contact allergens. It was done with
the aim that the test methods giving the clinically most relevant results
should be used in risk assessment of chemicals and in research.
A slightly modified multi-dose-response induction protocol was evaluated
with two model contact allergens when applied to three guinea pig
predictive test methods. The protocol was easily applied to the
cumulative contact enhancement test (CCET) and the Freund's complete
adjuvant test (FCAT), which have only one induction route. However, for
the guinea pig maximization test (GPMT) with two induction routes, the
topical doses at induction interacted with the logistic model. The
protocol would benefit from further development and some modifications
are suggested. Calculations of the estimated concentration sensitizing 50
% of the animals (EC 50 ) improves the possibility for proper ranking of
contact allergens and augments the information used in risk assessment.
The calculated EC 50 -values for the model allergens were: 0.00045 % in
the FCAT, 0.0025 % in the GPMT and 0.0042 % in the CCET for potassium
dichromate (K 2 Cr 2 O 7 ), and 0.068 % in the GPMT, 0.89 % in the FCAT
and 1.8 % in the CCET for hydroxycitronellal (HC).
A multi-dose-response induction protocol was applied on a modified mouse
ear swelling test (MEST) and evaluated with four contact allergens and
one irritant. This protocol could detect the moderate to strong contact
allergens as sensitizers, but not one (HC) of the two weak contact
allergens. The irritant (negative control) gave a Ônegative' response.
The EC 50 -values calculated for the three detected allergens were 0.002
% for oxazolone, 0.03 % for K 2 Cr 2 O 7 and 0.7 % for methyldibromo
glutaronitrile (MDBGN).
The murine local lymph node assay (LLNA) is a predictive test method, but
its ability to discriminate between allergens and irritants has been
questioned. Eight contact allergens and six irritants were investigated
in the evaluation of the LLNA. The moderate to strong allergens gave
clearly Ôpositive' results (stimulation index (SI) = 12.8 - 39.9), but
one weak allergen (benzocaine) was not classified as a sensitizer (SI<3).
The irritants tested, i.e. chloroform/methanol, methylsalicylate,
nonanoic acid, oxalic acid, sodium dodecyl sulfate (SDS), Triton X-100,
however, gave also Ôpositive' results (SI = 5.0 - 10.7), not
distinguishable from the results with weak and moderate contact allergens
(SI = 3.4 - 17.1). The addition of 10% SDS could not be used to reduce
the induced proliferation due to irritation from the test chemicals, nor
could an alternative choice of vehicle.
The allergenicity of a preservative, i.e. Euxyl K 400, and one of its
ingredients, MDBGN, was investigated in three different animal predictive
test methods, and patch testing in dermatitis patients was performed for
comparison. The CCET using57 a multi-dose-response induction protocol (EC
50 = 1.9 % for MDBGN) and the LLNA (SI = 7.4 - 7.9 for MDBGN and 8.4 -
12.0 for Euxyl K 400) confirmed the sensitization potential of the
substance based on dermatitis patients patch test results (total
frequency varied between 0.9 - 1.8 %). However, the results from the GPMT
were not statistically significant.
In conclusion, even though the LLNA and the MEST have some advantages
compared to the guinea pig test methods concerning speed,
labor-intensiveness and cost, and the use of an objective end point, the
methods are at present not capable of replacing the predictive guinea pig
test methods. Both the LLNA and MEST gave a lower sensitization rate with
the weak and moderate contact allergens tested than the guinea pig test
methods did. The MEST is judged to be less capable of detecting potential
contact allergens than the LLNA, but on the other hand no false
Ôpositive' reactivity with the irritant tested was seen. Dose-response
designs of predictive test methods increase the amount of information
obtained from each sensitization study and should be considered for
inclusion in the protocols used when the sensitizing potential of a
substance is investigated.
Investigators are advised to select the predictive test method with the
induction procedure that is most relevant for the prospected use of the
substance being tested. A test method with a particular induction route
may be more suitable for testing a substance than one of the recommended
methods, so there is also a possibility to use other available
standardized predictive animal test methods. However, that predictive
test methods have a varying capacity to detect the sensitizing potential
of a substance is evident.
List of papers:
I. Montelius J, Wahlkvist H, Boman A, Fernström P, Gråbergs L, Wahlberg JE (1994). "Experience with the murine local lymph node assay: inability to discriminate between allergens and irritants" Acta Derm Venereol 74(1): 22-7
Pubmed
II. Montelius J, Wahlkvist H, Boman A, Wahlberg JE (1998). "Murine local lymph node assay for predictive testing of allergenicity: two irritants caused significant proliferation" Acta Derm Venereol 78(6): 433-7
Pubmed
III. Wahlkvist H, Boman A, Lidén C (1999). "Dose-response studies of contact allergens using 3 guinea pigs models" Contact Dermatitis 41(4)
::
198-206
Pubmed
IV. Wahlkvist H, Boman A (1999). "Application of a dose-response protocol on the mouse ear swelling test (MEST) for contact allergy" (Submitted)
V. Wahlkvist H, Boman A, Montelius J, Wahlberg JE (1999). "Sensitizing potential in mice, guinea pig and man of the preservative Euxyl K 400 and its ingredient methyldibromo glutaronitrile" Contact Dermatitis 41(6): 330-8
Pubmed
I. Montelius J, Wahlkvist H, Boman A, Fernström P, Gråbergs L, Wahlberg JE (1994). "Experience with the murine local lymph node assay: inability to discriminate between allergens and irritants" Acta Derm Venereol 74(1): 22-7
Pubmed
II. Montelius J, Wahlkvist H, Boman A, Wahlberg JE (1998). "Murine local lymph node assay for predictive testing of allergenicity: two irritants caused significant proliferation" Acta Derm Venereol 78(6): 433-7
Pubmed
III. Wahlkvist H, Boman A, Lidén C (1999). "Dose-response studies of contact allergens using 3 guinea pigs models" Contact Dermatitis 41(4)
::
198-206
Pubmed
IV. Wahlkvist H, Boman A (1999). "Application of a dose-response protocol on the mouse ear swelling test (MEST) for contact allergy" (Submitted)
V. Wahlkvist H, Boman A, Montelius J, Wahlberg JE (1999). "Sensitizing potential in mice, guinea pig and man of the preservative Euxyl K 400 and its ingredient methyldibromo glutaronitrile" Contact Dermatitis 41(6): 330-8
Pubmed
Issue date: 1999-12-24
Publication year: 2000
ISBN: 91-7045-535-X
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