Regulatory Position And Biological Significance

In standard toxicology studies, there is no validated method to determine the autoimmune potential of a chemical. Regulatory agencies agree that the PLNA is useful for screening commercial candidates for T-cell activation. There is controversy, however, between the European and the US. agencies concerning the need for additional validation studies to assess PLNA's utility in predicting autoimmunity.

Chemicals are not routinely tested for their ability to induce immediate hypersensitivity reactions in animals. Agencies will request testing when (1) the test compound has structure-activity relationships to known allergens (e.g., pht-halates, isocyanates) or (2) the exposed population is very large. Most companies voluntarily perform tests to determine whether a new compound is more allergic than the one that it is replacing.

There is a critical need to develop and validate rapid, cost-effective in vivo or in vitro models that predict reactions in the lung or skin. Animal models for asthma should mimic the pathophysiology and immunopathology of the human disease in that (1) airway hyperactivity should be demonstrable either before or following antigenic challenge, (2) pulmonary function changes elicited by challenge with allergen should be consistent with reversible airway obstructive disease, and (3) the presence of allergen-specific IgE should be documented by serological assays or appropriate in vivo methods.

Tests for delayed hypersensitivity skin reactions are mandated by the EPA and OECD. However, Americans and Europeans differ on specific tests required for registration of chemicals. The EPA accepts data from either the BT or GPMT assay. Because methods using FCA are considered more sensitive than non-FCA sensitization protocols, the Europeans prefer that data from GPMT be submitted for registration of new compounds.

In Europe, arbitrary thresholds of^30% for the GPMT and >15% for the BT are used as a basis for sensitizer classification. The classification considers only the threshold and does not consider the intensity of the reaction. Moreover, the test results are not evaluated in the context of positive control data in the same assay (Basketter et al., 1993). Therefore, the data are treated the same regardless of whether the testing laboratory obtains a 30% or a 100% response with the positive control. If a chemical is classified a sensitizer, it must be labeled with the phrase "may cause sensitization by skin contact" (Anonymous, 1994).

In the United States, GPMT data are expressed as the sensitization rate (number of animals with a positive reaction/number of animals tested X 100). When 9-28% of the animals show a moderate and diffuse skin reaction (Grade II), the chemical is considered a mild sensitizer. A strong sensitizer has a 6580% sensitization rate with intense reddening and swelling. Reactions in the BT are graded differently. The sensitization incidence (number of animals showing a positive reaction/number of animals tested) and the reaction severity (sum of the test grades/number of animals tested) is determined. Slight, confluent erythema or moderate, patchy erythema (Grade I) reactions are considered sensitization unless the same response is seen in the controls.

Regulatory agencies recognize and accept data from alternate sensitization assays. The EPA accepts the MEST or the LLNA as screening assays to detect strong or moderate sensitizers. If a positive result is seen in either assay, the test substance would be designated a potent sensitizer and guinea pig tests would be unnecessary. If the LLNA or MEST does not indicate sensitization, accepted guinea pig studies must be used to confirm the results. Either the GPMT or the BT is acceptable to the agency as a confirmatory test.

Host defense and tumor models have been validated by the NTP. A major concern is that the models were validated in the mouse and most standard toxicology studies are performed in the rat. Efforts are currently under way to validate the host defense and tumor models in the rat.

How To Deal With Rosacea and Eczema

How To Deal With Rosacea and Eczema

Rosacea and Eczema are two skin conditions that are fairly commonly found throughout the world. Each of them is characterized by different features, and can be both discomfiting as well as result in undesirable appearance features. In a nutshell, theyre problems that many would want to deal with.

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