Redbook 2000: IV.B.3 Pathology Considerations in Toxicity StudiesToxicological Principles for the Safety Assessment of Food IngredientsRedbook 2000Chapter IV.B.3. Pathology Considerations in Toxicity Studies.

1. REDBOOK 2000: IV.B.3 PATHOLOGY
CONSIDERATIONS IN TOXICITY STUDIES
TOXICOLOGICAL PRINCIPLES FOR THE SAFETY
ASSESSMENT OF FOOD INGREDIENTS
REDBOOK 2000
CHAPTER IV.B.3. PATHOLOGY CONSIDERATIONS
IN TOXICITY STUDIES
Dmitri Popov, MD (Russia), PhD Radiobiology,
Advanced Medical Technology and Systems Inc.
Canada.

2. PATHOLOGY. PATHOLOGY.
 Pathology data make up an essential part of the toxicology
information submitted to FDA in support of the safe use of the use
of food ingredients.
The interpretation of pathology data and other safety data forms
the basis for judgement about the safety of a product.

3. TOXICOLOGY. PATHOLOGY.
 Specific recommendations concerning necropsy of test animals and
microscopic examination of organs and tissues for short-term
toxicity tests with rodents and non-rodents, sub-chronic toxicity
tests with rodents and non-rodents, one-year toxicity tests with
non-rodents, carcinogenicity studies with rodents, combined
chronic toxicity/carcinogenicity studies with rodents, reproduction
studies, and developmental toxicity studies can be found in
Chapter IV.B.1.e.

4. TOXICOLOGY. PATHOLOGY.
 Description of the Process for Review of Pathology Data.
 Review of pathology data may begin with a request for pathology
evaluation from regulatory review scientists or from the CAC. This
happens when questions about the interpretation of pathology
data arise during the scientific review of the toxicology
information submitted in support of the safety of food ingredients
.
 Requests for review are generally limited to specific interpretative
questions, directing the reviewing pathologist‘ attention to
findings in a particular organ or tissue. Occasionally, a reviewing
pathologist is asked to examine all of the pathology findings in a
study.

5. TOXICOLOGY. PATHOLOGY.
 The pathology portion of the study report usually contains mean
and individual organ weight parameters, clinical chemistry results,
hematological measurements, summary incidences of observed
pathological changes, and gross and microscopic pathology
observations for individual animals.
 An evaluation memorandum from the regulatory review scientist
may accompany the material; the memorandum contains
summaries of toxicology information, including the results of
previous toxicity studies and information from relevant scientific
literature.

6. TOXICOLOGY. PATHOLOGY.
 The reviewing pathologist:
 Determines how the percentage of animals with lesions in summary incidence tables has been
 calculated; for example, was the denominator based on the total number of animals in the study, or was
 it the number of animals for which a particular tissue or organ was examined microscopically;
 Compares gross and microscopic findings to ensure that all gross observations are accounted for by
 microscopic findings or by other suitable explanations;
 Examines the diagnostic terminology applied to lesions to determine whether it is contemporary and
 conventional;
 Checks to see that individual animal data provide adequate information on the location, size, and
 distribution of reported gross lesions;
 Considers the qualitative characteristics, severity of lesions, and the incidence figures in evaluating
 treatment-related differences among groups of experimental animals;
 Carefully evaluates control data before interpreting findings;
 Evaluates the discussion of significant pathological findings prepared by the study pathologist; and
 Correlates pathology findings, when appropriate, with other observations about treatment-related effects
 on test animals during the study.

7. TOXICOLOGY. PATHOLOGY.
 When the pathology review is completed, a formal written report is
submitted to the collaborating regulatory review scientist. The
report discusses the pathological findings based on review of
submitted material and the relationship of pathological findings to
treatment. If questions about the pathology data remain, the
report may recommend a request for additional, clarifying
material.