Acute phase response in toxicity studies. I. Survey of beagle dogs subjected to single-dose toxicity studies.
In the field of routine single-dose toxicity studies, we occasionally meet with transient leukocytosis associated with an increase in fibrinogen in beagle dogs within a few days after treatment with the test article. Only a little is known, however, about the toxicological significance of these changes. However, these changes were thought to belong to the category of "Acute Phase Response, APR," which has been known for a long time in connection with injury, trauma or infection. Aiming at proper understanding of these experiences, we surveyed 25 single-dose toxicity studies (7 intravenous bolus, 5 intravenous infusion, 12 oral and 1 subcutaneous treatment, hereafter referred to simply as i.v. bolus, i.v. infusion, oral and s.c.) in beagle dogs, provided with data from hematological examinations. We set the following criteria as a positive response in the present survey: increases of 50% or more in either or both WBC or fibrinogen compared to the predosing value, transiently from Day 1 to Day 3 of the study. Among 25 studies surveyed, about 1/2 of the studies exhibited increases of 50% or more in either or both fibrinogen or WBC counts compared to the predosing values showing dose-dependency transiently on Day 1 or Day 2. These changes were remarkable after intravenous application. Oral application produced similar effects, although the incidence and severity were low compared to the i.v. routes. Regarding blood chemical and hematological changes other than changes in fibrinogen and WBC counts, there were no essential differences between the groups of studies with and without the changes in fibrinogen and WBC counts. These changes were thought to be characteristic and to have occurred as incidents unrelated to other changes. The reported changes seen in single-dose toxicity studies may belong to the category of APR as the non-specific mechanism of living bodies as stated by Burns et al. (1996).
Hoshiya
T
T
Kannami Lab. Bozo Research Center Inc., 1308 Kuwahara-Sanbonmatsu, Kannami-cho, Tagatagun, Shizuoka 419-0101, Japan.
Watanabe
D
D
Akagi
K
K
Mizoguchi
Y
Y
Kamiya
K
K
Mizuguchi
H
H
Kumahara
M
M
Toya
H
H
Nagashima
Y
Y
Okaniwa
A
A
D000210:Acute-Phase Reaction / Q000097:blood; D000284:Administration, Oral; D000818:Animals; D001774:Blood Chemical Analysis; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005340:Fibrinogen / Q000032:analysis; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007958:Leukocyte Count; D007964:Leukocytosis / Q000097:blood / Q000139:chemically induced; D008297:Male; D012737:Sex Factors; D018675:Toxicity Tests
D005340:Fibrinogen