Human maximization test

Sensitization results are based on a human maximization test (103) usiag a petrolatum vehicle. The effect is expressed as the number of paneHsts responding over the total number of paneHsts tested and was 0/25 except for spearmint (0/32). That is, at the dose iadicated, the oils werenot irritating when tested ia a 48-h closed patch test ia humans. 

Basketter, D.A., Scholes, E.W. and Kimber, I., The performance of the local lymph node assay with chemicals identified as contact allergens in the human maximization test, Fd. Chem. Toxic., 32, 543, 1994. 

The Human Maximization Test was designed and later modified by Kligman et al. (1959, 1966). This test uses irritancy as an adjuvant. Irritating compounds... 

Results of RIPT, modified Draize test, and human maximization tests have been accepted as valid by regulatory agencies however, some sponsors routinely use one of the methods described and defend its use as the standard of the industry . FDA reviewed details of sensitization procedures and developed a guidance document (1999) for evaluating skin sensitization to chemicals in natural rubber products. 

The allergenic potencies were defined based on the percent responders in the human maximization test as follows (33) 10, Non-sensitizer 25, "marginal" (4-7% responders) 39, weak (8-23%responders) 49, "moderate" (24-66% responders) 59, "strong" (56-83% responders) 69, "extreme" (84-100%responders). 

Benzoyl peroxide is used mainly in acne treatment and is an irritant. Allergic contact dermatitis to this compound is not infrequent. Eaglstiein (1968) reported two cases. The sensitization rate has been estimated to be 1 %-2.5%. In a human maximization test, 76% became sensitized (Leyden and Kligman 1977). Crossreactions to benzoic acid and related compounds were not found. The drug has been advocated for treatment of chronic leg ulcers. Eight of 16 patients showed positive patch tests to 2% benzoyl peroxide after 6 weeks of leg ulcer treatment with 10% benzoyl peroxide (Jensen et al. 1980). Patients sensitized to benzoyl peroxide may be at risk in certain occupations (e.g., baking and the plastics industry). 

Guinea Pig Maximization Test One of a number of skin tests for screening possible contact allergens. Considered to be a useful model for predicting likely moderate and strong sensitizers in humans. 

The skin permeability of this chemical is low the log Kp value from the reasoning algorithm is -6.856 and the chemical is known to give a weak response in the guinea pig maximization test, which indicates an equivocal response in mammals. This information leads to the prediction from the software that skin sensitization in humans is doubtful. 

There are 4 basic predictive human sensitization tests in current use (1) single induction/ single challenge patch tests (2) repeated insult patch tests (RIPT) (3) RIPT with continuous exposure (modified Draize) and (4) the maximization test. Principal features of human sensitization assays are summarized in Table 2. 

Five sets of patches are worn on the same site for 48 h each, with a 24 h rest period between removal and reapplication. Following a 2 week rest period, an SLS provocative patch is applied to prepare the skin for challenge. A patch saturated with a 2.5-5.0 solution of SLS is applied to previously untreated sites on the lower back. SLS concentration is based on the season and on individual subject response. The SLS patch is removed after 1 hour, and a patch containing the test material is applied. A control site is patched with SLS (1 h) and petrolatum (48 h) to aid in interpretation of the results. The patch is removed 48 h after application. Test sites are evaluated at removal, and then reexamined 24 and 48 h after patch removal. The number of subjects developing a positive response is reported and a sensitization index based on percentage of subjects responding is assigned to the test material. In common practice, the human maximization procedure is performed on either the outer upper arm or the back. 

Kligman AM. The identification of contact allergens by human assay. III. The maximization test a procedure for screening and rating contact sensitizers. J Invest Dermatol 1966 47 393—409. 

There are several acceptable ways to evaluate DTH responses in nonclinical species. Of these, the most common are the guinea pig assays used to assess contact sensitization. Both the Magnusson and Kligman model (guinea pig maximization test) and the Buehler model measure the elicitation phase of the hypersensitivity response, though the tests vary in their methods of chemical application and utilization of adjuvants. Most recently, the local lymph node assay has been accepted as a stand alone test for chemical hypersensitivity. This assay is conducted in mice and measures the induction phase of sensitization. In humans, the most common methods to assess delayed hypersensitivity are the patch test (contact sensitivity for diagnostic purposes) and the human repeat insult patch test (contact sensitivity for predictive purposes). Additionally, intradermal... 

In the case of contact hypersensitivity, some difficulty arises in extrapolating from the animal sensitization test data to human sensitization risk. This is due to the fact that the published animal test data (primarily guinea pig maximization test results) generally indicate a sensitization potential far greater than the actual human experience would indicate. Lastly, methods for identifying compounds capable of autoimmune responses exist but have not yet been validated. 

Up to now, pulmonary sensitization cannot be examined in animal tests. For the examination of dermal sensitization, different test methods with different sensitiveness are available. For the examination of industrial chemicals, the so-caUed patch test applied to guinea pigs is usually sufficiently sensitive. In this, the test substance is administered directly to the skin, as in the human exposure situation. The maximization test, also called the Magnusson-Kligmann test (see Fig. 2.7) and developed originally for cosmetics and pharmaceuticals, is nowadays more and more used for chemicals also. A recently developed test method is the local lymph node assay (LLNA), which can be used to examine the potency of an allergen. 

Kappus H, Remmer H (1975) Irreversible protein binding of " C-imipramine with rat and human liver microsomes. Biochem Pharmacol 24 1079-1084 Kligman AM (1966) The identification of contact allergens by human assay. III. The maximization test a procedure for screening and rating contact sensitizers. J Invest Dermatol 47 393-409... 

There are four basic predictive human sensitization tests in current use (1) a single-induction/single-challenge patch test (2) repeated-insult patch test (RIPT) (3) RIPT with continuous exposure (modified Draize) and (4) the maximization test all of these use similar customized patches (Frosch and Kligman 1979 Kaminsky et al. 1986). Principal features of human sensitization assays are summarized in Table 1, and further details can be found in MarzuUi and Maibach (1996). For assays other than maximization, 150-200 subjects are usually tested. Henderson and Riley (1945) statistically showed that if no positive reactions are observed in 200 randomly selected subjects, as many as 15/1000 of the general population may react (95% confidence). As sample size is reduced, the likelihood of unpredicted adverse reactions in the general population increases. 

The drug should be administered at three levels by the route proposed for humans. The high dose level should be set so as to have relevance in humans. For drugs that display significant toxic effects, this may be related to the maximally tolerated dose in the toxicity tests, for example, the dose causing less than 10% deviation in body weight versus controls. If there is little evidence of toxicity it may be more appropriate to base the dose level on a multiple (usually 25-fold) of the maximum therapeutic dosage recommended in humans. 

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