Carcinogenic action of low‐dose cyclophosphamide given orally to sprague‐dawley rats in a lifetime experiment

Schmähl, D.

doi:10.1002/ijc.2910230518

Cited by 74 publications

(20 citation statements)

References 21 publications

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“…The State of California, under Proposition 65 legislation (CEPA 1993), has used the rat bladder tumor data from Schmahl and Habs (1979) to calculate a cancer slope factor of 0.57 (mg/kg/day) -1 . The corresponding no-significant-risk level (NSRL) is 1 µg/day (1 × 10 -5 excess cancer risk).…”

Section: Pharmaceuticals In the Aquatic Environmentmentioning

confidence: 99%

A Human Health Risk Assessment of Pharmaceuticals in the Aquatic Environment

Schulman

Sargent

Naumann

et al. 2002

Human and Ecological Risk Assessment: An International Journal

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Analyses were conducted on four pharmaceutical compounds, representing different therapeutic classes, to evaluate the presence and potential adverse human health effects of trace levels of these substances in aqueous environmental media. Acetylsalicylic acid, clofibrate, cyclophosphamide, and indomethacin have been detected in aqueous environmental media including sewage treatment plant effluent, surface water, drinking water, and groundwater. An extensive literature search and chemical-specific risk assessments were performed to assess the potential human health significance of each compound's individual presence in environmental media. Safe water quality limits were estimated for each pharmaceutical by following the USEPA Methodology for Deriving Ambient Water Quality Criteria for the Protection of Human Health and were compared to the concentrations found in the environment. The calculation of the provisional ambient water quality criteria involved estimation of human exposure to contaminated water, including intake via bioaccumulation in fish, and calculation of cancer risk and non-cancer hazard indices. Parameters detailing the toxicological and pharmacological nature, exposure assessment, and environmental fate and transport of each pharmaceutical were also considered. The overall conclusion was that based on available data, no appreciable risk to humans exists, as the detected concentrations of each of these pharmaceutical compounds found in aqueous media were far below the derived safe limits.

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Section: Pharmaceuticals In the Aquatic Environmentmentioning

confidence: 99%

A Human Health Risk Assessment of Pharmaceuticals in the Aquatic Environment

Schulman

Sargent

Naumann

et al. 2002

Human and Ecological Risk Assessment: An International Journal

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“…No excess risk of leukaemia was observed in association with radiotherapy for either ovarian or breast cancer patients. The present findings strongly suggest that cyclophosphamide as a single chemotherapeutic agent is capable of inducing leukaemia in humans.Cyclophosphamide is carcinogenic by several routes of administration in rats and mice (Schmahl & Habs, 1979; IARC, 1981). In humans there is also strong evidence that it is a carcinogen (Plotz et al, 1979;Elliot et al, 1982), producing tumours of the bladder and possibly other sites.…”

mentioning

confidence: 99%

“…Cyclophosphamide is carcinogenic by several routes of administration in rats and mice (Schmahl & Habs, 1979;IARC, 1981). In humans there is also strong evidence that it is a carcinogen (Plotz et al, 1979;Elliot et al, 1982), producing tumours of the bladder and possibly other sites.…”

mentioning

confidence: 99%

Risk of leukaemia in ovarian tumour and breast cancer patients following treatment by cyclophosphamide

Haas¹,

B²,

Wh³

et al. 1987

Br J Cancer

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Summary A case-control study was conducted to determine whether the development of leukaemia was associated with chemotherapy for neoplasms of the ovary or breast, in a population where most such chemotherapy consisted of cyclophosphamide alone. Cases and controls were identified from the National Cancer Registry of the German Democratic Republic. Cases were women who had developed leukaemia as a second primary after an initial diagnosis, at least one year before, of an ovarian or breast tumour. Controls were patients with an ovarian tumour or breast cancer who had survived to the year when the case developed a leukaemia but who had not themselves developed a second malignancy. Controls were matched to cases by the site of the first primary and its year of diagnosis, as well as year of birth. The relative risk for acute leukaemia following treatment with cyclophosphamide alone was significantly elevated (P<0.05), at 14.6 for ovarian tumour patients and 2.7 for breast cancer patients. Among breast cancer patients the increased risk of leukaemia associated with chemotherapy was confined to women who had been under 50 years of age at the time of diagnosis of the breast cancer (for whom the relative risk was 13.1). No excess risk of leukaemia was observed in association with radiotherapy for either ovarian or breast cancer patients. The present findings strongly suggest that cyclophosphamide as a single chemotherapeutic agent is capable of inducing leukaemia in humans.Cyclophosphamide is carcinogenic by several routes of administration in rats and mice (Schmahl & Habs, 1979; IARC, 1981). In humans there is also strong evidence that it is a carcinogen (Plotz et al., 1979;Elliot et al., 1982), producing tumours of the bladder and possibly other sites.There are a number of case reports of acute leukaemia following treatment with cyclophosphamide of nonmalignant diseases including rheumatoid arthritis, Wegener's granulomatosis, chronic glomerulonephritis, idiopathic thrombocytopaenia purpura, and Sj6gren's syndrome (Grunwald & Rosner, 1979). While cyclophosphamide is suspected to be a leukaemogen, it is widely believed to be less potent than many other nitrogen mustard-derived alkylating agents, and it is recommended as a component of adjuvant therapy following surgery for breast cancer (National Institutes of Health, 1986).Studies of leukaemia in cancer patients treated with cyclophosphamide have been difficult to interpret, because it is often given in combination with other agents known to be leukaemogenic. Although an increase in the risk of acute non-lymphocytic leukaemia (ANLL) following Hodgkin's disease has been appreciated for some time (Brody et al., 1977) it has not been possible to implicate directly cyclophosphamide, even though it has been widely used in Hodgkin's disease therapy (Boivin & Hutchison, 1984). Acute leukaemia also occurs in excess in patients with nonHodgkin's lymphoma who have undergone chemotherapy including cyclophosphamide (Pedersen-Bjergaard et al., 1985). In a study of multiple myeloma...

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“…DCE produced kidney tumors in male mice (13 (25). In that study, total doses ranged from 475 to 1,270 mg/kg body weight compared to the average 18-mo total of 98 mg received by our trout, which weighed an average of 450 g at the end of the experiment.…”

Section: Dcementioning

confidence: 99%

“…This report presents results of 9-and 18-mo dietary exposures of rainbow trout to single doses of 2,6-dimethylnitrosomorpholine (DMNM), which causes primarily esophageal and nasal turbinate tumors in rats (12), pancreatic ductal tumors in Syrian golden hamsters (23), and hemangiosarcomas of the liver in guinea pigs, when added to the drinking water (22); N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), a stomach carcinogen in rodents when administered in drinking water (4,26,29); 1,2-dibromoethane (DBE), a soil and grain fumigant and antiknock agent in leaded gasolines, which causes squamous cell carcinomas of the forestomach in rats and mice by oral intubation (18,19) and skin and lung tumors in mice after repeated skin application (30); 1,1-dichloroethylene (vinylidene chloride; DCE), an intermediate in the synthesis of many commercially important plastics that is noncarcinogenic to rats by inhalation exposure (12, 20, 21, 31 ) but causes kidney, lung, stomach, and skin tumors in mice, also by inhalation exposure (13,30); and cyclophosphamide (CP), an antineoplastic agent and immunomodulator causing leukemia and carcinoma of the urinary bladder after oral exposure in rats (25).…”

Section: Introductionmentioning

confidence: 99%

Carcinogenicity of Dietary Dimethylnitrosomorpholine, N-methyl-N'-Nitro-N-Nitrosoguanidine, and Dibromoethane in Rainbow Trout

et al. 1995

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Eighteen-mo feeding trials of rainbow trout were used to test the carcinogenicity of 5 chemicals in this species. A single exposure level was used for each substance. The doses and chemicals tested were 1,556 ppm 2,6-dimethylnltrosomorpholine (DMNM), 500 ppm N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), 2,000 ppm 1,2-dibromoethane (DBE), 2,000 ppm 1,1-dichloroethylene (DCE), and 200 ppm cyclophosphamide (CP). Liver and/or glandular stomach neoplasms were produced by DMNM (liver and stomach), MNNG (stomach), and DBE (chiefly, stomach tumors). In addition, DMNM produced a low incidence of swimbladder papillomas and caused testicular atrophy in 50% of treated males. DCE and CP produced no neoplasms at the exposure levels used. No evidence of other chronic toxicity was seen for any of the 5 compounds.

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Carcinogenic action of low‐dose cyclophosphamide given orally to sprague‐dawley rats in a lifetime experiment

Cited by 74 publications

References 21 publications

A Human Health Risk Assessment of Pharmaceuticals in the Aquatic Environment

A Human Health Risk Assessment of Pharmaceuticals in the Aquatic Environment

Risk of leukaemia in ovarian tumour and breast cancer patients following treatment by cyclophosphamide

Carcinogenicity of Dietary Dimethylnitrosomorpholine, N-methyl-N'-Nitro-N-Nitrosoguanidine, and Dibromoethane in Rainbow Trout

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