Aloe barbadensis Miller, Aloe vera, has enjoyed a long history of lay acceptance as an herbal remedy and is perhaps the most popular herbal remedy in use today. In recent times, the oral consumption of Aloe vera has been promoted as a prophylaxis and treatment to alleviate a variety of unrelated systemic conditions. The National Cancer Institute nominated Aloe vera for study under the National Toxicology Program, because of its widespread human exposure and because components in Aloe vera may possess tumor-promoting activities. Male and female F344/N rats and B6C3F1 mice were exposed to freeze dried (max. 6% moisture) and gamma-irradiated extracts of Aloe vera plant leaves in drinking water for 14 days, 13 weeks, or 2 years.
Fourteen-day study in rats
Groups of four male and four female F344/N rats were administered Aloe vera gel, Aloe vera nondecolorized whole leaf, or Aloe vera decolorized whole leaf extracts in drinking water at concentrations of 0, 0.5%, 1.0%, 1.5%, 2.0%, or 3.0% (wt/wt) for a period of 14 days. Rats were 7 weeks of age at the start of the dosed water treatment. All rats survived until the end of the study, and no nonneoplastic lesions were observed. The content of malic acid and aloin A were monitored throughout the study as markers for stability and dose certifications of the Aloe vera extracts.Aloe vera gel. The bulk Aloe vera gel extract test material had a malic acid content of 116 to 212 mg/g and an aloin A content of 1.1 to 1.4 mg/g. Mean body weights, body weight gains, water consumption, feed consumption, organ weights, and gastrointestinal transit times of exposed rats were similar to those of controls. Dose-related increases in urine glucose levels were observed in female rats. Serum levels of triglycerides, cholesterol, and albumin showed dose-related decreasing trends, and triglyceride levels were significantly lower than controls at Aloe vera gel concentrations of 1.5%, 2.0% in female rats and of 3.0% in male and female rats.
Aloe vera decolorized whole leaf. The bulk Aloe vera decolorized whole leaf extract test material had a malic acid content of 215 to 258 mg/g and the aloin A content was 0.06 to 0.2 mg/g. Mean body weights, water consumption, feed consumption, and organ weights, urine chemistry, and gastrointestinal transit times of exposed rats were similar to those of controls. Hematology and clinical chemistry values were similar to controls, with the exception of significantly lower blood urea nitrogen levels in female rats exposed 1.5%, 2.0%, and 3.0% levels of Aloe vera decolorized whole leaf extract.
Aloe vera nondecolorized whole leaf. The bulk Aloe vera nondecolorized whole leaf extract test material had a malic acid content of 188 to 197 mg/g and an aloin A content of 14.1 to 15.9 mg/g. The final mean body weights and body weight gains of rats in the 3.0% Aloe vera whole leaf groups were significantly less than those of controls; final mean body weights relative to controls were 79% in males and 81% in females. Water consumption by 3% Aloe vera whole leaf female rats and feed consumption by males exposed to 3.0% Aloe vera whole leaf extract were significantly less than those of controls. The liver, heart, spleen, thymus, and kidney weights of males and females exposed to 3.0% Aloe vera whole leaf extract were less than those of controls. Gastrointestinal tract transit times were shorter and urine volumes in male and female rats exposed to 3.0% Aloe vera whole leaf extract were lower than those of controls. Leukocyte and erythrocyte counts and hematocrit percentages were significantly elevated in male and female rats exposed to 3.0% Aloe vera whole leaf extract and creatinine and creatinine kinase values of 3.0% male rats were lower than control values.
Fourteen-day study in mice
Groups of four male and four female B6C3F1 mice were administered Aloe vera gel, Aloe vera decolorized whole leaf, or Aloe vera nondecolorized whole leaf extracts in drinking water at concentrations of 0, 0.5%, 1.0%, 1.5%, 2.0%, or 3.0% (wt/wt) for a period of 14 days. Mice were 7 weeks of age at the start of the dosed water treatment. All mice survived until the end of the study, and no nonneoplastic lesions were observed by histopathology.Aloe vera gel. The bulk Aloe vera gel extract test was identical to that used in the 14-day study in rats. Mean body weights, body weight gains, water consumption, feed consumption, organ weights, hematology, clinical chemistry, urine chemistry, and gastrointestinal transit times of exposed male and female mice were similar to those of controls.
Aloe vera decolorized whole leaf. The bulk Aloe vera decolorized whole leaf extract test material was identical to that used in the 14-day study in rats. Mean body weights, body weight gains, water consumption, feed consumption, organ weights, hematology, clinical chemistry, and urine chemistry, and gastrointestinal transit values of male and female mice were similar to controls.
Aloe vera nondecolorized whole leaf. The bulk Aloe vera nondecolorized whole leaf extract test material was identical to that used in the 14-day study in rats. Mean body weights, body weight gains, feed consumption, organ weights, hematology, clinical chemistry, urine chemistry, and gastrointestinal transit values of exposed male and female mice were similar to those of controls. Water consumption by male and female mice showed significant dose-related increasing trends, and water consumption was significantly higher than that by controls for female mice that received the 2.0% Aloe vera nondecolorized whole leaf.
Thirteen-week study in rats
Groups of 12 male and 12 female F344/N rats were administered Aloe vera nondecolorized whole leaf extract in drinking water at concentrations of 0, 1%, 2%, or 3% (wt/wt) for a period of 13 weeks. The bulk Aloe vera nondecolorized whole leaf extract test material had a malic acid content of 170.7 to 192.9 mg/g and an aloin A content of 12.6 to 14.4 mg/g.Two male and four female rats in the 2.0% and five male and eight female rats in the 3.0% Aloe vera nondecolorized whole leaf extract groups died or were removed due to morbidity before the end of the study. Final mean body weights and body weight gains of exposed male and female rats were significantly less than those of controls; final mean body weights of 3.0% Aloe vera whole leaf exposed groups were 71.8% of control levels for males and 77.4% of control levels for females. Water consumption by exposed male rats was higher than those of controls. Mean water consumption of 3% males was approximately twofold higher than that of controls. Average daily doses of Aloe vera whole leaf extract over the course of the study were 1.1, 2.7, and 3.8 g/kg body weight for male rats and 1.3, 4.0, and 3.2 g/kg body weight for female rats.
Volumes of 24-hour urine collections of male and female rats exposed to 2% Aloe vera nondecolorized whole leaf extract were significantly lower than those of controls, and urine creatinine and glucose levels were depressed. Decreased gastrointestinal transit times were observed in Aloe vera nondecolorized whole leaf exposed male and female rats; 2% male and female transit times were 4.3 and 6.2 hours, respectively, compared to 11.5 and 11.0 hours for control male and female rats, respectively. Hematology values for leukocyte counts, neutrophil percent, and erythrocyte counts were significantly elevated in male and female rats when compared to controls, and cholesterol and albumin levels were lower than those of controls. Absolute organ weights for brain, liver, heart, spleen, and thymus of rats exposed to 2% and 3% Aloe vera nondecolorized whole leaf extract were significantly less than those of controls. The incidences and severities of goblet cell hyperplasia in the large intestine of male and female rats exposed to Aloe vera whole leaf extract were increased compared to controls. There were no incidences of goblet cell hyperplasia of the large intestine in control male rats and an incidence of one (1/12, 8.3%) in the cecum of control female rats; incidences were 100% for male and female rats treated with the 2% or 3% Aloe nondecolorized whole leaf extract.
Thirteen-week study in mice
Groups of 12 male and 12 female B6C3F1 mice were administered Aloe vera nondecolorized whole leaf extract in drinking water at concentrations of 0, 1%, 2%, or 3% (wt/wt) for a period of 13 weeks. The bulk Aloe vera nondecolorized whole leaf extract test material was identical to that used in the 13-week study in rats.All mice survived until the end of the study. Mean body weights of exposed groups were similar to those of controls. Water consumption by female mice exposed to Aloe vera nondecolorized whole leaf extract was significantly higher than that of controls. Average daily doses of Aloe vera nondecolorized whole leaf extract over the course of the study were 3.7, 7.3, and 9.1 g/kg body weight for male mice and 3.7, 7.6, and 9.5 g/kg body weight for female rats. Gastrointestinal transit times of exposed 3% mice were similar to those of controls. Significant increases in 24 hour urine levels of creatinine and micro protein were observed compared to those of controls. The incidences and severities of goblet cell hyperplasia in the cecum and large intestine of male and female mice exposed to Aloe vera whole leaf extract were increased compared to controls.
Two-year study in rats
Groups of 48 male and 48 female F344/N rats were administered Aloe vera nondecolorized whole leaf extract at concentrations of 0, 0.5%, 1.0%, or 1.5% (wt/wt) in drinking water. The bulk Aloe vera nondecolorized whole leaf extract test material had a malic acid content of 186 to 203 mg/g and an aloin A content of 5.7 to 7.2 mg/g.Survival of all exposed groups of male rats was generally similar to that of controls. Reduced survival was observed for the 1.5% female dose group. Mean body weight gains of 1.5% groups of exposed female rats were less than that of the control group. Significantly lower feed consumption was observed for the 1.5% Aloe vera nondecolorized whole leaf extract treatment groups of male and female rats when compared to those of controls; daily feed consumptions over the 104 week study were approximately 90% of control levels. Water consumptions by male rats exposed to 1.0% and by male and female rats exposed to 1.5% Aloe vera nondecolorized whole leaf extract were significantly higher than those of controls. Mean daily water consumptions of 1.0% and 1.5% male rats in the 104 week study were 27 and 31 g, respectively for males; mean daily water consumption of male control rats was 22 g.
Treatment-related neoplasms and nonneoplastic lesions that occurred in the rat were primarily in the large intestine. Incidences of carcinomas of the ascending colon in 1.5% Aloe vera nondecolorized whole leaf extract groups of male rats were higher than that of controls. The incidences of adenomas of the proximal colon in 1.0% and 1.5% groups of male and 1.5% group of female rats were higher than that in controls. Incidences of adenomas of the transverse colon in 1.0% male rats were higher than those in the control groups. The incidences of all adenomas, all carcinomas, or the combined incidences of adenomas and carcinomas of the proximal, cecum, ascending, and transverse colon were significantly higher in the 1.0% and 1.5% groups than those of controls in both male and female rats. Incidences of adenoma or carcinoma combined were 17% and 31% in female rat 1.0% and 1.5% Aloe vera nondecolorized whole leaf extract groups, respectively, and 58% and 65% in male rat 1.0% and 1.5% Aloe vera whole leaf extract groups, respectively. Neoplasms of the large intestine were not observed in control animals.
In male and female rats exposed to Aloe vera whole leaf extract, dose-related incidences of mucosal hyperplasia of the proximal colon, cecum, ascending, transverse, and descending colon sites were significantly higher than those in controls. The incidences of cystic mesenteric lymph node degeneration and cecal dilatation were higher in the 1.0% and 1.5% Aloe vera nondecolorized whole leaf extract groups of male and female rats than those in controls.
Two-year study in mice
Groups of 48 male and 48 female B6C3F1 mice were administered Aloe vera nondecolorized whole leaf extract at concentrations of 0, 1.0%, 2.0%, or 3.0% (wt/wt) in drinking water for 2 years. The bulk Aloe vera nondecolorized whole leaf extract test material was identical to that used in the 2-year study in rats.Survival of all exposed groups was similar to that of controls. Mean body weight gains of male mice were less than that of controls, but ranged from 93% to 95% of control body weights. Feed consumption by 2.0% and 3.0% Aloe vera nondecolorized whole leaf extract mouse groups was higher than that by controls. Polydipsia was pronounced in both sexes administered the Aloe vera nondecolorized whole leaf extract, and water consumption by male and female mice exposed to Aloe vera nondecolorized whole leaf extract ranged from approximately 150% to 260% of control levels and equated to average daily doses of 2.5 to 11 g of Aloe vera nondecolorized whole leaf extract/kg body weight.
There were no significant increased incidences of neoplasms in mice in response to the Aloe vera nondecolorized whole leaf extract treatment in the drinking water. Treatment related increasing trends in the incidences of goblet cell hyperplasia were observed in the colons of male and female mice. The significance of this finding is uncertain.
Genetic toxicology
Three types of Aloe vera formulations were tested for mutagenicity in bacterial test systems employing a variety of different strains, with and without induced rat or hamster liver exogenous metabolic activation enzymes. The three formulations were Aloe vera gel, Aloe vera whole leaf extract (native), and Aloe vera charcoal filtered whole leaf extract. None of the three formulations showed any evidence of mutagenicity in bacteria, and none were cytotoxic when tested up to the limit dose of the assay.Conclusions
Under the conditions of these 2-year studies, there was clear evidence of carcinogenic activity of a nondecolorized whole leaf extract of Aloe vera in male and female F344/N rats based upon increased incidences of adenomas and carcinomas of the large intestine.There was no evidence of carcinogenic activity in male or female B6C3F1 mice exposed to 1%, 2%, or 3% (wt/wt) Aloe vera nondecolorized whole leaf extract in drinking water.
Exposure to a nondecolorized whole leaf extract of Aloe vera resulted in increased incidences of nonneoplastic lesions of the large intestine in male and female rats and mice, the small intestine in male and female rats, the stomach in male and female rats and female mice, the mesenteric lymph nodes in male and female rats and male mice, and the nose in male mice.