Aristolochic Acids

/HUMAN EXPOSURE STUDIES/ Chinese-herb nephropathy is a progressive form of renal fibrosis that develops in some patients who take weight-reducing pills containing Chinese herbs. Because of a manufacturing error, one of the herbs in these pills (Stephania tetrandra) was inadvertently replaced by Aristolochia fangchi, which is nephrotoxic and carcinogenic. The diagnosis of a neoplastic lesion in the native urinary tract of a renal-transplant recipient who had Chinese-herb nephropathy prompted us to propose regular cystoscopic examinations and the prophylactic removal of the native kidneys and ureters in all our patients with end-stage Chinese-herb nephropathy who were being treated with either transplantation or dialysis. Surgical specimens were examined histologically and analyzed for the presence of DNA adducts formed by aristolochic acid. All prescriptions written for Chinese-herb weight-reducing compounds during the period of exposure (1990 to 1992) in these patients were obtained, and the cumulative doses were calculated. Among 39 patients who agreed to undergo prophylactic surgery, there were 18 cases of urothelial carcinoma (prevalence, 46%; 95% confidence interval, 29 to 62%): 17 cases of carcinoma of the ureter, renal pelvis, or both and 1 papillary bladder tumor. Nineteen of the remaining patients had mild-to-moderate urothelial dysplasia, and two had normal urothelium. All tissue samples analyzed contained aristolochic acid-related DNA adducts. The cumulative dose of aristolochia was a significant risk factor for urothelial carcinoma, with total doses of more than 200 g associated with a higher risk of urothelial carcinoma. The prevalence of urothelial carcinoma among patients with end-stage Chinese-herb nephropathy (caused by aristolochia species) is a high.

/CASE REPORTS/ Mild to moderate atypia and atypical hyperplasia of the urothelium were detected in three women in Brussels, Belgium, who had undergone nephroureterectomies as part of a transplantation program. All three cases of end-stage renal disease were attributed to the use of Chinese herbs containing aristolochic acids. One of the three women developed, 12 months after transplantation, at the age of 25 years, two papillary tumors of the posterior bladder wall, histologically classified as low-grade transitional-cell carcinomas, without invasion. Microscopic transitional-cell carcinomas of low-to- intermediate grade were also detected in the two ureters (right and remnant distal part of left ureter) and in the right pelvis.

/CASE REPORTS/ At least 100 cases of extensive interstitial fibrosis of the kidneys were observed in Belgium in women who had followed a weight-loss regimen that included the use of Chinese herbs. The possible relation between the renal disease and these Chinese herbs was investigated. It was shown that the prescribed Chinese herb called Stephania tetrandra was, in fact, inadvertently replaced by another Chinese herb, namely Aristolochia fangchi in the powdered extracts delivered in Belgium and in France.

/CASE REPORTS/ A bilateral multifocal transitional-cell urothelial carcinoma occurring six years after the onset of end-stage renal disease was described in one of two cases of Chinese herbal nephropathy in the United Kingdom related to aristolochic acid from Aristolochia manshuriensis contained in Mu Tong.

For more Human Toxicity Excerpts (Complete) data for ARISTOLOCHIC ACIDS (7 total), please visit the HSDB record page.

/LABORATORY ANIMALS: Acute Exposure/ Groups of 5-6 male Fischer 344 rats, weighing 140-150 g, were given a single intraperitoneal injection of 10 mg/kg body weight aristolochic acids (a commercially available mixture of aristolochic acids I and II) 18 hours after a two-thirds partial hepatectomy. After a one-week recovery period, one group was kept on the basal diet while the second group was given a diet with 1% orotic acid to stimulate cell proliferation. In the second group, the percentage of rats with nodules and the number of nodules per rat were increased compared with the group given aristolochic acids alone, suggesting that aristolochic acids act as initiating agents.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ A group of 39 female NMRI mice (age not specified was given daily doses of 5.0 mg/kg body weight aristolochic acids (77.2% aristolochic acid I and 21.2% aristolochic acid II) by gavage for three weeks. A group of 11 vehicle controls was given solvent (unspecified). The mice were kept for up to 56 weeks interim sacrifice at 3, 9, 18, 26, 37 and 48 weeks. The remaining eight animals were killed at 56 weeks. At 18 and 26 weeks stages, low- to middle-grade papillomatosis was observed in the forestomach of all mice. Of the mice sacrificed at 37 and 48 weeks, 1/5 mice at each time point had squamous cell carcinoma. Forestomach carcinoma was diagnosed in all of the eight mice killed at 56 weeks. Adenocarcinoma of the glandular stomach was observed in one mouse at 37 weeks. In addition, cystic papillary adenomas in the renal cortex (6/8 mice), malignant lymphomas (4/8 mice), alveologenic carcinomas (8/8 mice) and hemangiomas in the uterus (3/8 mice) were found at 56 weeks. No tumors were detected in 11 control animals at 56 weeks.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Two groups of male Wistar rats, eight weeks old, were examined for the histogenesis of forestomach carcinoma caused by aristolochic acids (77.2% aristolochic acid I and 21.2% aristolochic acid II). A group of 108 rats was given aristolochic acids daily by gavage at a dose of 10 mg/kg in distilled water for up to 90 days. A group of 37 controls received distilled water. The animals were sacrificed sequentially. Administration of the aristolochic acids caused extensive necrosis of the squamous epithelium in the forestomach, followed by regeneration and hyperplasia, papilloma formation and ultimately invasive squamous-cell carcinoma. No pathological changes were seen in the controls.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Groups of 30 male and 30 female Wistar rats, 10 weeks of age, were given aristolochic acids (77.2% aristolochic acid I and 21.2% aristolochic acid II) as their sodium salts in distilled water at 10.0 or 1.0 mg/kg body weight for three months and held for up to an additional six months or at 0.1 or 0 mg/kg body weight for 3, 6 or 12 months and held for up to an additional four months. Forestomach carcinomas were observed in 13/18 males and 8/13 females given 10 mg/kg body weight for three months and killed at six months. In addition, renal pelvis carcinomas (8/18) and urinary bladder carcinomas (3/18) were observed in the males given 10 mg/kg body weight. Forestomach carcinomas were observed in 4/4 female rats treated with 10 mg/kg body weight for three months and killed at nine months. In the groups dosed with 1.0 mg/kg body weight for three months, forestomach carcinomas were observed in 3/11 males and 0/10 females after six months and 6/9 males and 2/11 females after nine months. In rats treated with 0.1 mg/kg body weight for three months and killed at 12 months, 2/7 males and 0/6 females and forestomach carcinomas. In rats treated with 0.1 mg/kg body weight for 12 months and killed at 16 months, 4/4 males and 1/5 females had forestomach tumors. Only one tumor (a spontaneous endometrial polyp) was observed in the controls (0/30 in males and 1/31 in females).

For more Non-Human Toxicity Excerpts (Complete) data for ARISTOLOCHIC ACIDS (8 total), please visit the HSDB record page.

Evaluation: There is limited evidence in humans for the carcinogenicity of naturally occuring mixtures of aristolochic acids. There is sufficient evidence in experimental animals for the carcinogenicity of aristolochic acids. Overall evaluation: Naturally occurring mixtures of aristolochic acids are probably carcinogenic to humans (Group 2A).

Evaluation: There is sufficient evidence in humans for the carcinogenicity of herbal remedies containing plant species of the genus Aristolochia. There is no data in experimental animals on the carcinogenicity of herbal remedies containing plant species of the genus Aristolochia. Overall evaluation: Herbal remedies containing plant species of the genus Aristolochia are carcinogenic to humans (Group 1). /Herbal remedies containing plant species of the genus Aristolochia/

Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

Presentation depends on the active toxic agent. In most cases, vomiting, abdominal pain, and diarrhea occur within 60 to 90 minutes of significant ingestion. With some toxins, severe gastroenteritis may result in massive fluid and electrolyte loss. ... Maintain open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, arrhythmias, and hypotension if they occur. Replace fluid loss caused by gastroenteritis with intravenous crystalloid solutions. ... Administer activated charcoal if available ... Gastric emptying is not necessary if activated charcoal is given promptly. /Plants and Herbal Medicines: Group 1/

LD50 Mouse (male) iv 38.4 mg/kg /Aristolochic Acid I/

LD50 Mouse (female) iv 70.1 mg/kg /Aristolochic Acid I/

LD50 Mouse ip 14.3 mg/kg

LD50 Mouse (male) oral 55.9 mg/kg /Aristolochic Acid I/

For more Non-Human Toxicity Values (Complete) data for ARISTOLOCHIC ACIDS (9 total), please visit the HSDB record page.