An evaluation of carcinogenicity predictors from short-term and sub chronic repeat-dose studies of agrochemicals in rats: Opportunities to refine and reduce animal use

Abstract

The aim of this study was to examine whether short term, repeat dose, rat studies provide sufficient information about potential carcinogenicity to enable predictions about the carcinogenic potential of agrochemicals to be made earlier in compound development. This study aimed to identify any correlations between toxicity findings obtained for short term rat studies (28 day and 90 day) and neoplastic findings obtained from 24 month rat carcinogenicity studies for agrochemical compounds (18 compounds) tested in Han Wistar and Sprague Dawley rats. The macroscopic pathology, microscopic pathology, hematology, biochemistry, organ weights, estrogen receptor activation and genotoxicity results were examined. Seven out of 18 non genotoxic compounds developed tumors in treated rats in the carcinogenicity study and of these, two compounds showed no preneoplastic findings in the affected tissues (false negatives). Of the remaining five true positives, correlations were noted between corneal opacity and keratitis (90 day study) as early indicators of squamous cell carcinoma and papilloma of the cornea of the eye (compound 1, a hydroxyphenylpyruvate dioxygenase inhibitor) and inflammation of the stomach and kidney (90 day study) and gastric squamous cell papilloma and squamous cell carcinoma and renal tubular adenoma and carcinoma, respectively (compound 12, a fungicide with multisite activity). Minor decreases in uterine weight and increases in estradiol hydroxylation activity at 28 days were associated with endometrial adenocarcinoma (compound 18, a mitochondrial complex II electron transport inhibitor). Early liver weight increases and hepatocellular centrilobular hypertrophy (28 day study) were associated with thyroid follicular adenomas (compound 11, a succinate dehydrogenase inhibitor) in female animals only. Hepatic centrilobular hypertrophy (28 day studies) correlated with thyroid adenomas in males in carcinogenicity studies (compound 2, a hydroxyphenylpyruvate dioxygenase inhibitor). In contrast, treatment related, nasopharynx tumors (compound 3, an elongase inhibitor) and uterine adenocarcinoma (compound 9, a succinate dehydrogenase inhibitor) could not be correlated with findings from the short term studies examined. Eleven compounds displayed preneoplastic findings with no tumors (false positives) and there were no compounds with no preneoplastic findings and no tumors (true negatives). This work indicates the value of examining historical, short term studies for specific, nonneoplastic findings which correlate with tumors in carcinogenicity studies, which may obviate the need for further animal carcinogenicity studies.

Keywords: Biochemistry; Carcinogenicity; Hematology; Organ weights; Pathology; Predictive; Rat; Tumors.