Frequency and relationships of clinical chemistry and liver and kidney histopathology findings in 13-week toxicity studies in rats.
The relative sensitivities of eight commonly used clinical chemistry end points and histopathology to detect potential toxic effects in liver and kidney were evaluated for a series of 61 13-week rat toxicity studies conducted for the National Toxicology Program. The data consisted of 1-,2- to 3-, and 13 week clinical chemistry measurements and 13-week histopathological assessments of liver and kidney. Except for serum alkaline phosphatase, treatment-related alterations of individual clinical chemistry variables occurred in 20-48% of the studies, depending on the analyte, sampling time, and sex. Liver and kidney lesions were reported for 31% and 41% of the studies respectively. There was an association between treatment-related increases in alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities and histopathological changes in the liver. SDH activity had greater positive and negative predictive values than similar changes in ALT; by week 1 in females and weeks 2-3 in both sexes. SDH predicted morphological hepatic change at study termination with 75% or better accuracy. If increases in activities of both enzymes occurred simultaneously, however, terminal histopathological changes could be predicted, in both sexes, with 75% accuracy by week 1, increasing to 100% by weeks 2-3. There also was an association between treatment-related increases in urea nitrogen (UN) and creatinine (Cre) concentrations and morphological kidney change. Cre concentration had greater positive predictive values than similar changes in UN; by weeks 2-3 in males and week 13 in both sexes. Cre predicted morphological renal change at study termination with 56% or better accuracy. UN concentration was associated and predictive of morphological kidney change only in females at week 13. Depending on time point and sex, serum alkaline phosphatase activity increased in 5-22% of the studies. Increases in total bile acid concentration occurred in 33-48% of the studies. Because both tests are used as markers of cholestasis, this marked discrepancy was unexpected. Treatment-related decreases in alkaline phosphatase activity occurred, however, in 39-56% of the studies; serum alkaline phosphatase may be more useful as an indicator of decreased food intake (decreased activity) than of cholestasis (increased activity). In summary, treatment-related alterations of clinical chemistry and histopathology occurred frequently in this series of toxicity studies in rats. Changes in the chemistry end points also occurred frequently at interim time points, indicating that clinical chemistry evaluations can be useful for detecting potential treatment effects throughout a study. This observation is important, since histopathological evaluations are limited to animal termination and not useful for detecting transient responses or the onset of treatment-related effects.
Travlos
G S
GS
Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709, USA.
Morris
R W
RW
Elwell
M R
MR
Duke
A
A
Rosenblum
S
S
Thompson
M B
MB
D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D001647:Bile Acids and Salts / Q000032:analysis; D015415:Biomarkers / Q000032:analysis; D001798:Blood Proteins / Q000032:analysis; D001806:Blood Urea Nitrogen; D056486:Chemical and Drug Induced Liver Injury; D002624:Chemistry, Clinical; D003404:Creatinine / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D007668:Kidney / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D007674:Kidney Diseases / Q000139:chemically induced; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012680:Sensitivity and Specificity; D012709:Serum Albumin / Q000032:analysis; D018675:Toxicity Tests / Q000379:methods*
D001647:Bile Acids and Salts; D015415:Biomarkers; D001798:Blood Proteins; D012709:Serum Albumin; D003404:Creatinine; D007064:L-Iditol 2-Dehydrogenase; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase