Biomedical subjects

L Blaikie

Publications and source records attributed to L Blaikie.

7 recordsLinked to original sources

PubMed2002

Dose-time relationships for elicitation of contact allergy to para-phenylenediamine.

Skin-sensitizing chemicals exhibit dose-response relationships for the elicitation of contact dermatitis. Previously, considerable work has been carried out in which the elicitation of allergic skin reaction has been examined as a function of the applied concentration. However, the relationship between exposure time, dose and response has not been explored in any depth. The present work has extended our initial assessment of the relationship between both exposure time and concentration for para-phenylenediamine (PPD) in a group of 19 PPD-allergic volunteers. The results clearly demonstrate that a relationship exists between both exposure time and concentration. Positive responses to PPD were directly proportional to exposure time: at 5 min 16% responded; at 15 min, 38%; at 30 min, 50%; and at 120 min, 69%. A similar direct relationship was found between concentration of PPD and response: after 120 min, 22% of patients had responded to 0.01%, and 69% to 1% PPD. All exposures for 1 and 2 min were negative. Subsequent evaluation using repeated 5 min open application testing demonstrated a cumulative effect, as after 8 days 39% of the panel reacted, more than double the number that reacted to a single occluded 5-min treatment. It was noted that there was marked subject variability in exposure time and dose required to elicit an allergic response. These results are of relevance for the general interpretation of patch test data, especially with regard to risk assessment.

Adolescent↗

PubMed2000

Activity of human contact allergens in the murine local lymph node assay.

The murine local lymph node assay (LLNA) is a predictive test for the identification of chemicals that have the potential to cause skin sensitization. Since its original development, the assay has been the subject of national and international evaluation studies and extensive comparisons with guinea pig tests and human data. On the basis of these investigations, the LLNA has recently been endorsed by ICCVAM (Interagency Coordinating Committee on the Validation of Alternative Methods) as a stand-alone method for skin sensitization hazard identification. At the same time, ICCVAM confirmed that, although the LLNA is not an in vitro method, it does represent a refinement in the way animals are used and can provide a means for reducing the number of animals used in sensitization hazard assessment. The investigations described here were designed to explore further the ability of the LLNA to identify accurately those chemicals that cause allergic contact dermatitis in humans. To that end we have measured, amongst 3 independent laboratories, LLNA responses induced by a total of 18 test chemicals, 11 of which are known to cause skin sensitization and 7 of which are believed not to be associated with any significant evidence of allergic contact dermatitis in humans. The LLNA correctly classified 16 of the 18 materials. The 11 chemicals tested which are associated with allergic contact dermatitis in humans were found to be positive in the LLNA. Of the 7 materials believed to be non-sensitizers, 5 were negative in the LLNA and 2 produced positive results. Collectively, these data provide additional evidence that the LLNA is able to discriminate skin sensitizers from those chemicals which do not possess a significant skin sensitization potential and thus provides a method for hazard identification that offers important animal welfare benefits.

Allergens↗

PubMed1999

Experience with a mouse intranasal test for the predictive identification of respiratory sensitization potential of proteins.

The predictive identification of respiratory allergenic potential is an important primary step in the safety evaluation of (novel) proteins, such as the enzymes used in a range of consumer laundry products. In the past this has been achieved by assessing the relative ability of proteins to give rise to the formation of anaphylactic antibody in the guinea pig. Recently, an alternative model has been proposed which assesses the formation of specific IgG1 antibody in a mouse intranasal test (MINT), the assumption being that specific IgG1 antibody is a surrogate for anaphylactic antibody in the mouse. This procedure has undergone successful initial intralaboratory and interlaboratory assessment. In the present work, the MINT has been evaluated in a more thorough intralaboratory study using eight enzymes plus ovalbumin. While the data generated with a reference enzyme protein, Alcalase, showed good reproducibility, results with the remaining eight proteins led to estimates of their relative antigenic or sensitization potential several of which were at variance from those derived from the guinea pig/ human experience. In consequence, it is concluded that the MINT requires substantial further investigation before it can be adopted as a model for the assessment of the relative ability of proteins to behave as respiratory allergens.

Administration, Intranasal↗

PubMed1999

Strain variation in the IgG1 antibody response to proteins administered intranasally in the mouse.

Proteins, including enzymes, have the potential to behave as respiratory allergens. In consequence, guinea pig methods have been developed which permit an assessment to be made of their respiratory allergenic/antigenic potential relative to an appropriate reference substance. Recently, a murine model, the mouse intranasal test (MINT) has been proposed as a potential alternative. However, to be of value, the new method should give a rank order of relative potency for a range of proteins which correlates with that found in guinea pig models and in human experience. Using the mouse strain recommended for the MINT, BDF1, in an extensive intralaboratory assessment, the relative potency of several of the eight proteins used was at variance with that expected from the historic data. Where genetic factors are important, as in the assessment of antigenicity, the rank order for a range of proteins in a particular inbred or F1 hybrid strain may not reflect that in humans. To examine whether the earlier observations were a strain rather than a species dependent phenomenon, five proteins of varying antigenic potency previously tested using the BDF1 strain were selected and tested using the MINT protocol in BALB/c, CBA/Ca and CB6F1 inbred/F1 hybrid strains, as well as in the outbred Swiss S strain. The results clearly indicated that the relative potency of the proteins was dependent on the mouse strain used and thus with haplotype. When assessed against the standard reference enzyme, Alcalase (a process used for the establishment of occupational exposure guidelines), the rank order was strain dependent and results from none of the mouse strains would have led to similar conclusions to those derived from existing models and the human epidemiological data. Based on the presently available information, it is not possible to be certain that any mouse model reliant on the responsiveness of a particular strain (including the MINT) might not lead to an incorrect estimation of respiratory antigenic and thus allergenic potency. In consequence, the MINT may not be viable as a model for the assessment of the relative ability of proteins to behave as respiratory allergens.

Administration, Intranasal↗

PubMed1996

The impact of atopic status on a predictive human test of skin irritation potential.

There has been much interest in recent years in the replacement of the Draize rabbit skin test for the identification of chemical skin irritants. A considerable effort has gone into the development of cell culture based assays. However, where ethical and safety considerations permit, the most obvious alternative is to use man himself. Data obtained using a suitable assay based on the endpoint of concern in the species of concern should be accurate and will represent a vital data base on which to develop sound in vitro assays. Thus, it is important to ensure the data produced in human assays is representative for man generally. To this end we have chosen to examine a number of variables and in this work report the effect of atopic status on the results obtained in a recently described human 4-h patch test. 30 atopic (defined by specific IgE to common allergens and by elevated total IgE) and 28 non-atopic volunteers were tested in this human 4-h patch test using 20% sodium dodecyl sulfate (SDS), 10% hydrochloric acid (HCl) and undiluted cocotrimethyl ammonium chloride (coco TAC). The level of irritant reaction was higher for SDS in the atopic panel, but was similar for HCl and coco TAC. The rank order of irritancy was the same in both panels. The results indicate that, whilst the intensity of reactions may be higher in atopics, their pattern of responses is similar to non-atopics. There is no evidence to indicate that they should either be deliberately included or excluded from the test panels recruited on a routine basis.

Animal Testing Alternatives↗

PubMed1995

Occupational asthma caused by automated salmon processing.

Within 3 months of the opening of a salmon-processing plant in the UK, some workers complained of symptoms suggestive of occupational asthma. A survey of all 291 employees identified 24 (8.2%) with occupational asthma. The employees worked near machines which generated respirable aerosols containing salmon-serum proteins. The IgE response to these proteins was associated with occupational asthma (p < 0.001), with increasing severity of symptoms (p < 0.001), and with working distance from the aerosol source (p = 0.037). The main factor which predisposed to IgE-antibody production and asthma was cigarette smoking (p < 0.001), whereas atopy and a previous allergic history did not. The affected employees were reallocated to a low-exposure worksite and factory ventilation was improved. Eleven showed significant clinical and pulmonary function improvement, and continued in employment. Thirteen who still had symptoms were advised to leave, thereafter becoming symptom-free, and regaining normal respiratory function. Early recognition of symptoms and prompt action to reduce aerosol exposure avoided the long-term reduction in pulmonary functions often associated with occupational asthma.

Adult↗

PubMed1995

A two-centre study for the evaluation and validation of an animal model for the assessment of the potential of small molecular weight chemicals to cause respiratory allergy.

This study evaluated a single intradermal injection model in the guinea pig with subsequent inhalation challenge and serological analysis as a method to predict the potential of chemicals to induce respiratory allergy. Four known respiratory allergens (trimellitic anhydride, diphenyl methane diisocyanate, phthalic anhydride and toluene diisocyanate (TDI)) were screened by two industrial research laboratories using this protocol. Dinitrochlorobenzene, a potent contact allergen, was included as a negative control material. In both laboratories, the respiratory allergens, but not the contact allergen, induced high titre antigen-specific antibodies in treated animals. The inhalation challenge results were similar in both laboratories but were less conclusive in that exposure to free TDI failed to induce pulmonary responses, probably because it fails to penetrate to the deep lung in sufficient concentration. Although the assay shows promise as a means of identifying chemical respiratory sensitisers, its use as a routine screen for the prediction of the ability of materials to induce respiratory allergy in man is probably questionable.

Administration, Inhalation↗