a-Chaconine and a-solanine were nominated for testing based on their frequent occurrence in high concentrations in commonly ingested foods and the lack of carcinogenicity data for either compound.

Both a-chaconine and a-solanine are glycoalkaloids which exhibit antifeedant, fungicide, and pesticide activities. a-Chaconine has been used as a nematicide, and both glycoalkaloids have been used in the treatment of asthma and epilepsy. a-Chaconine and a-solanine occur naturally in potatoes (Solanum tuberosum) and other members of the Solanaceae family. Solanine is also present in apples, bell peppers, cherries, sugar beets, and tomatoes.

The two glycoalkaloids are produced commercially by extracting the major alkaloids with water, and then preparing a crude glycoalkaloid extract from the weakly acidic plant extract. Both chemicals contain the same solanidine moiety, but differ in their attached trioses. Production and import volumes were not found.

Human exposure predominantly occurs via the consumption of foods containing a-chaconine and a-solanine. In 1993, the average annual per capita consumption of potatoes in the U.S. was estimated to be 61 kg, which correlates to an average daily consumption of 167 g of potatoes. The glycoalkaloid content in potatoes varies significantly depending on environmental conditions during growing, mechanical injury, length of storage, and potato variety. The average glycoalkaloid content is 0.075 mg/g potato. This, in turn, would result in the ingestion of 12.75 mg glycoalkaloids/ person/ day (0.18 mg/kg) based on the average per capita consumption and an average body weight of 70 kg. Deep frying at temperatures of 170°C is effective in lowering the glycoalkaloid levels. Boiling is not effective and microwaving is only slightly effective. Similarly, freeze drying and dehydration reduce the glycoalkaloid content of potatoes only slightly or not at all. Peeling reduces the quantity of glycoalkaloids in potatoes since 30 to 80% of the glycoalkaloids are found in the outer peel. Baked and fried potato peels are a major source of large quantities of a-chaconine and a-solanine in the diet.

Poisoning resulting from ingesting potatoes containing high levels of glycoalkaloids has been demonstrated in a number of case studies. Symptoms, which generally occur 8 to 12 hours after ingestion, include gastrointestinal disturbances and neurological disorders. One study analyzing case reports of poisoning determined that glycoalkaloid doses of 2 to 5 mg/kg (0.0023-0.0058 mmol/kg) induce toxic symptoms in humans, and doses of 3 to 6 mg/kg (0.0035-0.007 mmol/kg) are fatal.

In one epidemiologic study, a regional correlation between the severity of potato late-blight (which causes increased glycoalkaloid levels) and the incidence of congenital spina bifida was reported, but other studies found no correlation between the consumption of potatoes and the incidence of birth defects.

The relationship between the consumption of potatoes and cancer risk has been investigated but remains undetermined. Case-control studies reporting increased risks of digestive tract tumors (e.g., colon, esophagus, rectal, and stomach cancer) associated with high levels of potato consumption are matched by an equal number of studies reporting a decreased risk for these same cancers. Other studies have suggested that there is an increased risk for cancers of the brain, breast, endometrium, lung, and thyroid associated with the consumption of large quantities of potatoes, but a causal relationship between diet and cancer in these studies was not definitely proven.

Pharmacokinetic studies have shown that in humans, consumption of potatoes resulted in increased serum levels of a-chaconine, a-solanine, and the metabolite solanidine. Animal studies generally showed that a-chaconine and a-solanine are poorly absorbed. In mice, rats, and hamsters, a-chaconine and a-solanine reached peak tissue concentrations within 6 to 14 hours. Peak concentrations of a-solanine in plasma were reached in less than 35 hours. Tissues which accumulated a-chaconine and a-solanine included abdominal fat, adrenals, blood, brain, heart, kidney, liver, lungs, muscle, pancreas, spleen, testis, thymus, and thyroid. Both a-chaconine and a-solanine were excreted in the urine and feces (in varying amounts) either unchanged or as the metabolite solanidine. In vitro, rumen microorganisms were found to hydrolyze the glycoalkaloids to solanidine, much of which was then reduced to 5 b-solanidan-3b-ol. No solanidine was identified in the milk of cows fed tater meal (an animal feed known to contain high levels of glycoalkaloids).

Acute toxicity values for several species have been reported. For a-chaconine, the intraperitoneal (i.p.) LD₅₀ is 19.2 to 27.5 mg/kg (0.023-0.032 mmol/kg) for mice and 84 mg/kg (0.099 mmol/kg) for rats. For a-solanine, the oral LD₅₀ dose is 590 mg/kg (0.68 mmol/kg) for rats; the i.p. LD₅₀ dose is 30 to 42 mg/kg (0.035-0.048 mmol/kg) for mice, 67 to 75 mg/kg (0.077-0.086 mmol/kg) for rats, and less than 40 mg/kg (0.046 mg/kg) for monkeys. For rabbits, the i.p. LD_Lo dose is 50 mg/kg (0.059 mmol/kg) for a-chaconine and 40 mg/kg (0.046 mmol/kg) for a-solanine. The i.p. LD₅₀ dose for solanine hydrochloride is 42 mg/kg (0.046 mmol/kg) for mice.

Acute, short-term, and subchronic animal toxicity studies identified similar effects from administration of a-chaconine, a-solanine, or plants or extracts containing the glycoalkaloids. Effects on the nervous system included increased heart, pulse, and respiratory rates, sedation, and coma. Effects resulting from cell membrane disruption included internal hemorrhaging, edema, diarrhea, constriction of the abdominal muscles, and lesions of the stomach and duodenum. a-Chaconine was a potent cholinesterase inhibitor, and a-solanine exhibited weak to moderate cholinesterase inhibition. In some studies, hepatotoxic effects were induced. Concordant with human case reports and animal toxicity studies, in vitro studies also found that a-chaconine anda-solanine disrupted cell membranes and inhibited cholinesterase activity. No chronic exposure data were found.

a-Chaconine, a-solanine, or plants or extracts containing these glycoalkaloids were embryotoxic and teratogenic to experimental animals. Teratogenic effects in mammals were primarily central nervous system abnormalities (e.g., exencephaly, cranial bleb, encephalocele, and anophthalmia). Some studies found no neural tube defects, but reported a high incidence of other abnormalities, including mild hydronephrosis, hydroureter, and irregular or fused ribs. a-Chaconine appeared to exert teratogenic effects at lower doses than a-solanine.

No carcinogenicity data were found for either compound.

Limited genotoxicity data were found for a-chaconine and a-solanine. a-Chaconine was not mutagenic at concentrations up to 2300 mmol/plate in Salmonella typhimurium strains TA98 and TA100 with or without metabolic activation. However, analysis of pooled data from two experiments with a-chaconine in strain TA98 without metabolic activation suggested weak mutagenic activity. Based on data from multiple experiments, a-solanine at concentrations up to 2300 mmol/plate was not mutagenic in strains TA98 and TA100 with or without metabolic activation. In a DNA-Cell-Binding assay, solanine, at 25 or 250 M, did not increase the binding of radiolabeled DNA to Escherichia coli Q13 cells. When administered orally at 10 mg/kg to mice, a-[³H]chaconine did not covalently bind to DNA or RNA isolated from the livers. The only other genotoxicity data identified for these compounds was from a mouse micronucleus test. In this study, no increase was observed in the frequency of micronucleated erythrocytes in blood from weanling mice or fetuses from dams dosed i.p. with up to 45 mmol/kg a-chaconine and 90 mmol/kg a-solanine.

One immunologic study indicated that consumption of potato plants containing glycoalkaloids induced dermatitis in Indian buffaloes, while another study reported anti-allergic effects of intravenous (i.v.) administration of solanine hydrochloride to guinea pigs.

Studies conducted to evaluate other biological effects potentially relevant to this evaluation were reviewed. In vitro tests using isolated guinea pig ileum indicated a cholinergic action of a-chaconine and a-solanine. Solanine did not impede synaptic transmissions in isolated frog thoracic superficial muscle. In vitro studies using isolated frog ventricle or beating rat heart cell cultures found that solanine exerted a positive chronotropic effect and a-chaconine and a-solanine exerted a positive inotropic effect. Both glycoalkaloids were cytotoxic to Chinese hamster ovary cells. Solanine exhibited a hyperglycemic effect in intact rats and a hypoglycemic effect in adrenalectomized rats. a-Chaconine and a-solanine both increased ornithine decarboxylase activity in rats. Low concentrations of a-solanine stimulated the growth of cultured human fibroblasts by shortening the G₁ cell cycle phase. Higher concentrations inhibited fibroblast cell growth, and an abnormal accumulation of cells in the G₂ phase was observed. a-Chaconine inactivated Herpes simplex virus Type I in vitro.

In terms of structure-activity relationships, the biological activity of glycoalkaloids is influenced by the nature and the number of sugars composing the carbohydrate moiety attached to the 3-OH position of the aglycone, and the stereochemical orientation of the chaconine diglycosides. Embryotoxicity generally decreased with stepwise removal of sugar units from the chacotriose and solatriose side chains. Based on this relationship, the forms of the two glycoalkaloids, similar to each other in potency, are more potent than the b forms, which in turn are more potent than the g forms; solanidine, which contains no sugar units, is the least potent embryotoxin.

TABLE OF CONTENTS

1.0 BASIS FOR NOMINATION

2.0 INTRODUCTION

3.0 PRODUCTION PROCESSES AND ANALYSES

4.0 PRODUCTION AND IMPORT VOLUMES

5.0 USES

6.0 ENVIRONMENTAL OCCURRENCE AND PERSISTENCE

7.0 HUMAN EXPOSURE

8.0 REGULATORY STATUS

9.0 TOXICOLOGICAL DATA

10.0 STRUCTURE-ACTIVITY RELATIONSHIPS

11.0 ONLINE DATABASES AND SECONDARY REFERENCES

12.0 REFERENCES

ACKNOWLEDGEMENTS

TABLES

• Table 1 Acute Toxicity Values for a-Chaconine
• Table 2 Acute Toxicity Values for a-Solanine
• Table 3 Acute Toxicity Values for Solanine Hydrochloride
• Table 4 Acute Exposure to a-Chaconine and a-Solanine
• Table 5 Short-Term and Subchronic Exposure to a-Chaconine and a-Solanine
• Table 6 Embryotoxicity and Teratogenicity of a-Chaconine and a-Solanine
• Table 7 Genotoxicity of a-Chaconine and a-Solanine
• Table 8 Immunotoxicity of a-Chaconine and a-Solanine
• Table 9 Anti-Immunotoxicity of a-Solanine