Structural Assessments in Adult Animals

Macro- and/or microscopic structural anatomy of immune system organs and tissues are examined in a number of general guideline screening studies utilized by the U.S. EPA, including the acute inhalation toxicity study with histopathology (40 CFR 799.9135; USEPA 1997), the 90-day subchronic study (OPPTS 870.3100, 870.3150, 870.3250, 870.3465; USEPA 1998c-f), and the chronic/carcinogenicity studies (OPPTS 870.4100, 870.4200, 870.4300; USEPA 1998i-k).

In guideline subchronic and chronic/carcinogenicity studies, an evaluation of macroscopic structure and general qualitative histopathology is only conducted on a few immune system tissues. In subchronic studies that include young adult animals (e.g., rats 45 days to 5 months of age), the spleen, thymus, and lymph nodes from two locations (one near to and the other distal from the site of administration) are examined, and the spleen and thymus are weighed. In chronic and carcinogenicity study guidelines, there is no specification that the thymus be examined and/or weighed. For rodents (e.g., rats or mice 18 months to 2 years of age), it is reasonable to assume that the thymus would have undergone normal age-related atrophy by study termination. However, the thymus would be present at early interim sacrifices of rodents (e.g., at 6 months or 12 months of study) during a long-term study, and

Life Stages

Preconception

Guideline Study Designs:

Immunotoxicity Study

Skin Sensitization Study

Subchronic Study

Chronic/Carcinogenicity Study

Prenatal Developmental Toxicity Study

Reproduction and Fertility Study

Emb/ Prewean-

Fetai I ing I Juvenile I AdolescenceI

Adulthood

Old Age

Gross structure & weights of thymus/spleen, response to T cell-dependent antigen, SRBC (PFC or ELISA). Case-by-case: NKcell activity, total B cells, T cells, and T cell subpopulations im

Reaction to initial induction or challenge dose

Gross structure, thymus/spleen weights, spleen/thymus/lymph node (2 sites) histology

Organ weights, gross structure, histology

Gross structure, thymus/spleen weights, spleen/thymus/lymph node (2 sites) histology

Clinical pathology (differential WBC, serum immunoglobulin every 6 months)

Clinical pathology (differential WBC, serum immunoglobulin every 6 months)

Organ weights, gross structure, histology

Figure 3.1 Life stage at which immunotoxicity endpoints are assessed in guideline studies.

Ol it would certainly be present at study termination in a 1-year canine chronic toxicity study (at which point the dogs are young adults of approximately 1.5 years of age).

Differential white cell counts in the circulating blood are examined at study termination in the subchronic study and at approximately 6-month intervals in long-term studies. Serum immunoglobulin levels may be measured at the same intervals. Perturbations may indicate increased immune system response to some unspecified initiator, but this information does not address the adequacy of immune system function. In the same manner, histopathological evaluation of other organ systems in the subchronic and chronic/carcinogenicity studies may identify cellular alterations that are nonspecific indicators of an effect on immune response, for example, the presence of increased numbers of macrophages in lung tissue or an increased incidence of inflammatory dermal lesions.

In the chronic toxicity studies in rodents, aged animals are available for evaluation; however, only indirect evidence of perturbation of the immune system may be observed through macroscopic and microscopic evaluation of various organs. Corollary functional assessment is not performed in this population.

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