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Fumonisin B1 is a
mycotoxin produced by the fungus Fusarium moniliforme, one of the major species found in corn. There are no known commercial or medical uses of
fumonisin B1.
Fumonisin B1 was nominated by the FDA Center for Food Safety and Applied Nutrition for study because of its occurrence in corn and corn-based products in the United States and its toxicity in field exposure of horses and pigs. Male and female F344/N Nctr BR rats and B6C3F1/Nctr BR (C57BL/6N x C3H/HeN MTV-) mice were exposed to
fumonisin B1 (92% pure) in feed for 28 days or (greater than 96% pure) for 2 years. 28-DAY STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 99, 163, 234, or 484 ppm
fumonisin B1 for 28 days. There were no exposure-related deaths in rats. The mean
body weights of the 484 ppm groups were significantly less (-16%) than those of the controls. Dietary concentrations of 99, 163, 234, and 484 ppm
fumonisin B1 resulted in average daily doses of 12, 20, 28, and 56 mg
fumonisin B1/kg
body weight for males and females. Additional groups of male and female rats were exposed to the same concentrations of
fumonisin B1 for 28 days for clinical pathology studies. The concentrations of
creatinine,
cholesterol,
triglycerides, and total
bile acids, as well as activities of the
enzymes alanine aminotransferase,
alkaline phosphatase,
aspartate aminotransferase, and
gamma-glutamyltransferase, were generally significantly greater in the 484 ppm groups than in the control groups at all time points, indicating
hyperlipidemia and a hepatic effect.
Fumonisin B1 is an inhibitor of
ceramide synthase, resulting in an interruption of de novo
sphingolipid synthesis. This
enzyme inhibition results in increased levels of
sphinganine (or increased
sphinganine:
sphingosine ratio) in tissues and urine. Urinary
sphinganine was increased in groups of males exposed to 163 ppm or greater, while urinary
sphinganine was increased in all exposed groups of females. The kidney weights, relative to
body weight, of all exposed groups of rats were less than those of the control groups, decreasing by approximately 11% in the females and 20% in the males. Apoptosis and degeneration of the kidney were observed in all exposed males and in most females exposed to 163 ppm or greater. The incidences of minimal to mild apoptosis, degeneration, and mitotic alteration of the liver were significantly increased in 234 and 484 ppm males and in females exposed to 163 ppm or greater. The incidences of bile duct
hyperplasia were significantly increased in males and females in the 484 ppm groups. In the core study, male rats in all exposed groups and females exposed to 163 ppm or greater had significantly increased percentages of hepatocytes in one or more proliferative (non-G0) states. 28-DAY STUDY IN MICE: Groups of 12 male and 12 female mice were fed diets containing 0, 99, 163, 234, or 484 ppm
fumonisin B1 for 28 days. There were no exposure-related deaths in mice. The mean
body weights of the 484 ppm groups of males were significantly less than those of the controls. Feed consumption by males exposed to 484 ppm was less than that by the controls; dietary concentrations of 99, 163, 234, and 484 ppm
fumonisin B1 resulted in average daily doses of approximately 19, 31, 44, and 93 mg/kg for males and 24, 41, 62, and 105 mg/kg for females. Additional groups of male and female mice were exposed to the same concentrations of
fumonisin B1 for 28 days for clinical pathology studies.
Cholesterol and total
bile acid concentrations and
alanine aminotransferase and
alkaline phosphatase activities were increased at 484 ppm, indicating
hyperlipidemia and a hepatic effect. Urinary
sphinganine concentrations and
sphinganine/
sphingosine ratios were increased in 484 ppm male mice. In 484 ppm males and all exposed groups of females, the incidences of hepatocellular
necrosis, diffuse periportal
hypertrophy, and diffuse centrilobular
hyperplasia, as well as
hyperplasia of the bile canaliculi and Kupffer cells, were generally significantly greater than those in the controls. Core study males exposed to 99, 163, or 234 ppm had significantly increased incidences of hepatocellular cytoplasmic alteration. Hepatocytes of 484 ppm male mice and all exposed groups of female mice were induced into proliferative (non-G0) states. 2-YEAR STUDY IN RATS: Groups of 48 male and 48 female rats (40 for 5 ppm groups) were fed diets containing 0, 5, 15, 50, or 150 ppm
fumonisin B1 (males) or 0, 5, 15, 50, or 100 ppm
fumonisin B1 (females) (equivalent to average daily doses of approximately 0.25, 0.76, 2.5, or 7.5 mg/kg to males and 0.31, 0.91, 3.0, or 6.1 mg/kg to females) for 105 weeks. Additional groups of four male and four female rats were exposed to the same concentrations as the core study animals and were evaluated at 6, 10, 14 or 26 weeks. Survival,
Body Weights, and Feed Consumption Survival, mean
body weights, and feed consumption of exposed male and female rats were generally similar to the controls throughout the study. Clinical Pathology Findings
Sphinganine/
sphingosine ratios were increased in the urine of 15, 50 and 150 ppm males and 50 and 100 ppm females exposed to
fumonisin B1 for up to 26 weeks. The
sphinganine/
sphingosine ratios were also increased in kidney tissue of 50 and 150 ppm males (85- and 119-fold) and 50 and 100 ppm females (7.8- and 22-fold) at 2 years. Cell Proliferation Analyses Renal tubule epithelial cell proliferation was increased in 50 and 150 ppm male rats exposed to
fumonisin B1 for up to 26 weeks. Renal tubule epithelial cell proliferation was marginally increased in 100 ppm females. Organ Weights and Pathology Findings Kidney weights of 50 and 150 ppm males were less than those of the controls at 6, 10, 14, and 26 weeks and at 2 years. Kidney weights of 100 ppm females were less than those of the controls at 26 weeks, and kidney weights of 15, 50, and 100 ppm females were less than those of the controls at 2 years. At 2 years, there was a significant increase in the incidences of renal tubule
adenoma from none in the groups receiving 15 ppm or less to five of 48 in 150 ppm males. Renal tubule
carcinomas were not present in male rats receiving 15 ppm or less and occurred in seven of 48 and 10 of 48 male rats in the 50 and 150 ppm groups, respectively. Incidences of apoptosis of the renal tubule epithelium were generally significantly increased in males exposed to 15 ppm or greater for up to 26 weeks. The incidences of focal renal tubule epithelial
hyperplasia were significantly increased in 50 and 150 ppm males at 2 years. 2-YEAR STUDY IN MICE: Groups of 48 male and 48 female mice were fed diets containing 0, 5, 15, 80, or 150 ppm (males) or 0, 5, 15, 50, or 80 ppm (females)
fumonisin B1 (equivalent to average daily doses of approximately 0.6, 1.7, 9.7, or 17.1 mg/kg to males or 0.7, 2.1, 7.1, or 12.4 mg/kg to females) for 105 weeks. Additional groups of four male and four female mice were exposed to the same concentrations as the core study animals and were evaluated at 3, 7, 9, or 24 weeks. Survival,
Body Weights, and Feed Consumption Survival of males and females in the 15 ppm groups and of 5 ppm females was significantly greater and survival of 80 ppm males and females was significantly less than that of the control groups. Mean
body weights and feed consumption of exposed mice were generally similar to the controls. Organ Weights and Pathology Findings Liver weights, relative to
body weight, were increased 1.3- and 2.9-fold in 50 and 80 ppm females at 2 years. At 2 years, the incidences of
hepatocellular adenoma in 50 and 80 ppm females were significantly greater than those in the controls and occurred with a positive trend. Similarly, the incidences of
hepatocellular carcinoma increased from none in the groups receiving 0, 5, or 15 ppm
fumonisin B1 to 10 of 47 females at 50 ppm and nine of 45 females at 80 ppm. The incidences of hepatocellular
hypertrophy were significantly increased in 15, 80, and 150 ppm males and in 50 and 80 ppm females at 2 years. The incidences of hepatocellular apoptosis were significantly increased in 50 and 80 ppm females at 2 years.
CONCLUSIONS: