Retrorsine

Readily hydrolyzed with alkali; reacts with oxidizing agents (slowly with atmospheric oxygen) to form dihydropyrrolizine and other derivatives.

Hydroxyl radical reaction rate constant = 2X10-10 cu cm/molec-sec @ 25 °C /Estimated/

/HUMAN EXPOSURE STUDIES/ The two main sources of pyrrolizidine alkaloid poisoning reported in human beings are the consumption of cereal grain contaminated by weeds containing the alkaloids and the use of alkaloid-containing herbs for medicinal and dietary purposes. ...Three of the largest outbreaks of the disease have been reported from South Asia, two from the same site in central India and one from North-West Afghanistan. The first Indian outbreak... occurred in a group of 5 tribal villages in central India in 1972-73. ...Out of a total population of 2,060 in these villages, 71 households with 366 members were investigated. Among these, 39 cases had developed and 19 had died before commencement of the investigations. The incidence rate was 1.1% and the case fatality rate was 50%. All cases occurred among 20 households. In many households, several members were affected. In one household, 4 out of 5 cases died. ...The etiological factor of this outbreak was not established, though dietary contamination with pyrrolizidine alkaloids was considered. A second outbreak occurred at the same site in 1975... . A total population of 486 was affected, 67 cases were reported, of whom 28 (46%) had died. There was a strong family history... . In a later survey, 108 patients were studied and the mortality rate was estimated to be 63%. This time the etiological factor was identified as the plant Crotalaria nana Burm, which had been growing in the fields of millet (Panicum miliare), their staple food crop. The seeds of this plant became mixed with the cereal grain during harvesting. The toxic seeds contained pyrrolizidine alkaloids that were identified as a macrocyclic ester closely similar to monocrotaline. The total alkaloid content was estimated to be 5.3 g/kg of seed, expressed as monocrotaline. The levels of contamination of the millet with seeds were reported to be 0-3.4 g/kg in the unaffected and 0-19 g/kg in the affected households... . /Pyrrolizidine alkaloids/

/HUMAN EXPOSURE STUDIES/ The largest outbreak reported to date occurred in the Gulran district of Herat Province in northwest Afghanistan, close to the border of the USSR. ...The outbreak, was estimated to have affected a population of approximately 35,000 in 98 villages. Examination of 7,200 inhabitants of the affected villages showed evidence of disease in 22.6%, which was more serious in 15%. Thus, it was estimated that approximately 8,000 subjects suffered from the disease including 5,000 who were seriously affected. All age groups were affected, but 46% of subjects were below 14 years of age. However, no sign of disease was found in children below 2 years of age. A detailed report concerning the pathological material obtained from 14 liver biopsies and 8 autopsies was made... /although/ the time interval between the onset of symptoms and the biopsy/autopsy was not indicated. Pathological findings were characteristic, ranging from acute disease with characteristic veno-occlusion to non-portal cirrhosis, which was observed in 5 of the above 22 cases. The outbreak was ascribed to massive contamination of wheat, the staple food crop, following 2 years of drought, with the seeds of Heliotropium popovii H. Riedl subsp. gillianum H. Riedl, which had been growing profusely among the wheat crop. The seeds contained pyrrolizidine alkaloids at concentrations reported by 2 laboratories to be 7.2 and 13.2-14.9 g/kg, identified mainly as the N-oxide of heliotrine (74%)..., and one or two other compounds similar in character to lasiocarpine. Samples of wheat from several villages contained an average of 40 seeds/kg, i.e., 0.03% by weight. It was estimated that an adult consumed at least 700 g flour/day, containing approximately 2 mg alkaloid (based on a mean of the seed analyses). /Pyrrolizidine alkaloids/

/HUMAN EXPOSURE STUDIES/ Human consumption... occurs from Symphytum and Senecio species in some herbal preparations, such as "comfrey tea" or "groundsel tea". /Pyrrolizidine alkaloids from Senecio species/

/SIGNS AND SYMPTOMS/ Retrorsine is one of the main alkaloids present in the Senecio species which have contaminated grain in South Africa and so caused the often fatal 'bread poisoning' of humans in South Africa. The most common symptoms were severe abdominal pain, rapidly developing ascites and hepatomegaly. In some outbreaks there were extreme emaciation, nausea, and diarrhea.

For more Human Toxicity Excerpts (Complete) data for RETRORSINE (6 total), please visit the HSDB record page.

Retrorsine

Group 3: Not classifiable as to its carcinogenicity to humans

Volume 10: (1976) Some Naturally Occurring Substances

1987

1987

/LABORATORY ANIMALS: Acute Exposure/ Administration of 40 mg/kg body weight retrorsine by stomach tube to rats caused a severe and rapid inhibition of the synthesis of liver and serum proteins.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Suckling rats died with severe liver and other typical pyrrolizidine-induced lesions when their mothers were given 20-84 mg/animal retrorsine in doses of 5-10 mg orally or ip twice weekly or more often. The mothers survived, although liver lesions developed.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ Female Wistar rats with new-born litters were fed either control or a retrorsine (50 mg/kg) diet. At 0, 4, 8, 11, 15, 18 and 21 days, pups from each litter were weighed, sacrificed and their livers removed for copper, DNA and metallothionein analysis. Serum samples were assayed for caeruloplasmin oxidase activity and albumin. ... Retrorsine passing to rat neonates via breast milk causes: the accumulation, of hepatic copper, impairment of the rise in serum caeruloplasmin, which could indicate a decline in synthesis or failure of copper incorporation into the apo-protein, a decrease in hepatic metallothionein and serum albumin levels, again suggesting diminished protein synthesis, and reduced hepatic DNA indicative of decreased cell number but increased cell size. Accumulation of liver copper but reduction of copper-binding proteins could result in free copper and explain the synergistic hepatotoxicity of copper and retrorsine.

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Most studies have examined the effects in the liver; the tumors produced are mostly of epithelial origin, but a significant number are also vascular. Possible types of tumor include: hepatomas; hepatocellular carcinoma with metastases; mammary tumors; lung carcinoma; renal carcinomas; colonic carcinoma; splenic hemangioendothelioma; osteosarcoma bone; leukemia; 'spindle cell" tumor (neck); uterine carcinoma; retroperitoneal sarcoma; and squamous cell carcinoma (of the jaw) were described for retrorsine. /Pyrrolizidine alkaloids/

For more Non-Human Toxicity Excerpts (Complete) data for RETRORSINE (12 total), please visit the HSDB record page.

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 iv 59 mg/kg

LD50 Rat ip 34 mg/kg

LD50 Rat iv 38 mg/kg

In animal studies highest concentrations were found in the liver, lungs, kidneys and spleen. /pyrrolizidine alkaloids/

When pyrrolizidine alkaloids, retrorsine 60 mg/kg, retrorsine n-oxide 60 mg/kg were administered ip to rats, 0.2-12.4% of the doses were excreted in the urine within 24 hr as metabolic pyrroles. There was a rough correlation between the hepatotoxicity of alkaloids and the amount of pyrroles to which they gave rise to in vivo. When rats were dosed orally or ip with retrorsine 50 mg/kg and sacrificed after various times, metabolic pyrroles were found bound strongly to the liver, and to /lesser/ extent the lung and other organs, for 48 hr or more after being formed.