Mononuclear cell leukemia

In an animal study of rats exposed by inhalation to ethylene oxide at 10, 33, or 100 ppm for approximately two years (245), and in a separate chronic rat study in which rats were exposed to 50 or 100 ppm of ethylene oxide (240), increased incidences of mononuclear cell leukemia, peritoneal mesothelioma, and various brain tumors have been reported. In an NTP (246) two-year inhalation study of mice at 50 and 100 ppm, alveolar/bronchiolar carcinomas and adenomas, papillary cystadenomas of the harderian gland, and malignant lymphomas, uterine adenocarcinomas, and mammary gland tumors were increased in one or both exposure groups. 

Lymphomas in mice Mononuclear-cell leukemia in rats (mainly F344)... 

In studies conducted using animals, evidence of carcinogenicity from 1,4-dichlorobenzene exposure is based on 2-year oral studies in mice and rats. 1,4-Dichlorobenzene was administered by gavage to male rats at doses of 150 mg/kg/day and 300 mg/kg/day, and to female rats and mice of both sexes at doses of 300 mg/kg/day and 600 mg/kg/day. There was a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidneys of male rats. There were no tubular cell tumors in dosed or vehicle-control female rats. There was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats compared with either vehicle controls or historical controls (NTP 1987). Based on the finding of renal tumors in this study, 1,4-dichlorobenzene was found to be carcinogenic in male rats. 

Mononuclear Cell Leukemia (MNCL) is unique to the rat, and is only common in the F-344 (common name Fischer rat) inbred rat strain, which is the strain used by the U.S. National Toxicology Program (NTP). Elevated incidences of MNCL have been observed in a number of chronic bioassays in the F-344 rat. The frequency differs between males and females, with an incidence in males around 50%, and an incidence in females around 30%, with a large variation from study to study. It has been shown for some genotoxic carcinogens that exposure does not lead to an increase in MNCL in the F-344 rat, while a number of substances, which are believed to be noncarcinogens,... 

Caldwell, D.J. 1999. Review of mononuclear cell leukemia in F-344 rat bioassays and its significance to human cancer risk A case study using alkyl phthalates. Regul. Toxicol. Pharmacol. 30 45-53. 

Although several epidemiological studies have suggested a positive association between dichlorvos exposure and cancer, conclusions are limited because all have involved small study groups and exposure to several agents. In animal studies chronic gavage administration of dichlorvos caused a dose-related increase in papillomas of the forestomach in mice and a dose-related increase in mononuclear-cell leukemia and an increased incidence of pancreatic acinar cell adenomas in male rats. The lARC has determined that there is sufficient evidence for the carcinogenicity of DDVP in experimental animals and inadequate evidence in humans. ... 

In a chronic inhalation bioassay in rats exposed for 6 hours/day, 5 days/week for 2 years to 100, 33, or 10ppm ethylene oxide, there was a dose-related increased occurrence of mononuclear cell leukemia in both sexes at all concentrations. There was also an increased occurrence of primary brain tumors at 100 and 33 ppm in both sexes and peritoneal mesotheliomas arising from the testicular serosa at 100 and 33 ppm in male rats. ... 

In 2-year studies rats were given 0, 25, or 50mg/kg hydroquinone by gavage 5 days/ week whereas doses for mice were 0, 50, or lOOmg/kg on the same schedule. There was evidence of carcinogenicity in male rats as indicated by increased incidences of tubular cell adenomas of the kidney, in female rats as shown by increases in mononuclear cell leukemia, and in female mice based on increases in hepatocellular neoplasms, mainly adenomas. There was no evidence of carcinogenicity in male mice. 

Large gavage doses, approximately 500 and lOOOmg/kg per day for 78 weeks, caused a statistically significant increase in the incidence of hepatocellular carcinomas in mice. Inhalation exposure by rats to 200 or 400 ppm for 2 years caused an increased incidence of mononuclear cell leukemia a dose-related trend for a rare renal tubular neoplasm was observed in males. ... 

Isophorone produced kidney effects in male rats in the NTP (1986) study. Strasser (1988) found that isophorone caused protein droplet formation in the kidneys of male rats, suggesting that isophorone can induce protein nephropathy. Alden (1986) discussed the possibility that proteinuric humans and humans with low molecular weight protein nephropathy, such as people with multiple myeloma (Bence-Jones protein) or mononuclear cell leukemia (lysozyme), may be more susceptible to chemically-induced protein nephropathy. He concluded, however, that this syndrome is probably specific to the male rat. 

Tumors were not clearly or consistently observed in nonhepatic tissues of animals exposed to FireMaster FF-1. Induction of thyroid follicular cell adenoma was inconclusive in mice in both National Toxicology Program bioassays. Equivocal increases in incidences of mononuclear cell leukemia were observed in adult-only exposed rats in the NTP chronic study, and combined perinatal and adult exposure showed no significant increase. Combined analysis of the incidences of this leukemia in the adult-only, perinatal only. 

Cancer is generally considered the critical endpoint for chronic exposures. In lifetime studies, rats exposed to airborne concentrations of 10, 33, or 100 ppm for 6hday , 5 days week exhibited several treatment-related tumors including mononuclear cell leukemia, peritoneal mesothelioma, and... 

In a rabbit study, hydroquinone at 150 mg kg day produced minimal developmental alterations in the presence of maternal toxicity. The no-observed-effect level for developmental toxicity was 75mgkg day In rat studies, maternal toxic effects from exposure to hydroquinone included changes in the ovaries, fallopian tubes, and menstrual cycle. Postimplantation mortality was also observed in rat studies. Observed paternal toxic effects from exposure to hydroquinone included changes in the testes, epididymis, sperm duct, prostate, seminal vesicle, Cowper s gland, accessory glands, and male fertility index. Further, exposure to hydroquinone produced skeletal malformations in chickens and ocular and skeletal malformations in rabbits. Hydroquinone can induce renal tubule adenomas, bladder carcinomas, hepatocellular neoplasms, and mononuclear cell leukemia in experimental animals. 

Chronic oncogenicity studies in animal models have led to methylene chloride being classified as an animal carcinogen. In treated mice, hepatocellular carcinomas and broncho/alveolar neoplasm have been reported to be significantly elevated over controls, while salivary gland sarcomas have been noted in male rats and increased incidences of leukemia and mammary adenomas found in female rats. Other lesions found in oncogenicity studies include mesotheliomas at multiple sites, mononuclear cell leukemias and hemangiomas. 

A 2 year drinking water smdy performed in rats and mice showed hepatocellular injury by week 13 and clear evidence of carcinogenic activity in all animals that survived 1 year or longer. Renal tubule neoplasms, mononuclear cell leukemia, hepatocellular neoplasms, and interstitial cell adenoma of the testis were noted. Human... 

As a result of National Toxicology Program (NTP) bioassays, PERC has been reported to produce hepatocellular carcinomas in B6C3F1 mice of both sexes when administered by gavage. An NTP inhalation study also showed hepatocellular carcinomas in B6C3F1 mice and renal cell adenomas and adenocarcinomas and mononuclear cell leukemias and renal tubular cell neoplasms in Fisher 344 rats. 

M (CEL pancreatic islet cell adenoma, pituitary chromophobe adenoma, mononuclear cell leukemia)... 

LOEL 250 mg/kg/day (mice) 125 mg/kg/day [10, 11] (rats) hepatocellular hypertrophy NOEL 10 mg/kg/day increases in liver and [1] kidney weights, increases in the incidence of hepatocellular hypertrophy, increases in thyroidparathyroid weights, hypertrophy and hyperplasia of the thyroid high incidences of trace-to-mild chronic nephritis in kidneys of male rats and increased pigmentation of the renal tubules in female rats LOAEL = 312 mg/kg/day (rats) 125 mg/kg/day [10, 11] (mice) hepatocellular neoplasms and adenomas or adenocarcinomas of the liver mononuclear cell leukemia adenomas or hyperplasia of the renal tubular cells in exposed male rats follicular cell adenomas or carcinomas of the thyroid in exposed female rats and female mice alveolar/bronchiolar adenomas or carcinomas in male mice 52 mg/kg Paroil intestinal activities of aryl [13] hydrocarbon hydroxylase (increase), UDP-glucuronosyltransferase (decrease) and epoxide hydrolase (increased)... 

Hepatocellular degeneration and necrosis occurred in male mice exposed to 100 and 200 ppm tetrachloroethylene for 103 weeks and in females exposed to 200 ppm. Liver effects were not reported in rats exposed chronically to 200 or 400 ppm tetrachloroethylene, but the effects of mononuclear cell leukemia infiltrates may have obscured subtle compound-induced changes (NTP 1986). Both sexes of mice also had increased incidences of hepatocellular tumors at both exposure concentrations. This study is discussed further in Section 2.2.1.8. 

Low incidences of renal tubular cell adenomas or adenocarcinomas (1/49, 3/49,4/50) occurred in male rats (NTP 1986). Although the incidence of these tumors was not statistieally signifieant, the fact that there was any increase was itself significant because these tumors are considered uncommon in untreated male rats. In mice of both sexes exposed to 100 or 200 ppm, there were significantly increased incidences of hepatocellular neoplasms (Table 2-2). Study limitations include numerous instances of rats and mice loose from their cages within the exposure chambers, with the potential for aberrations in exposure and animal identification, as well as a very high incidence of mononuclear cell leukemia in control rats, and liver tumors in mice. 

Despite some indication of human risk of leukemia from solvent exposure, the relevanee to human health of elevated incidences of mononuclear cell leukemia related to tetraehloroethylene exposure in Fischer-344 rats is unclear. This is a spontaneous and very prevalent neoplasm that is fairly specific for Fischer-344 rats, and the control incidences for this study were higher than historical values. However, NTP s Board of Scientific Counselors considered the ineidenee of rat leukemias to be a true finding because there was a decreased time to onset of the disease and the disease was more severe in treated as compared to eontrol animals. 

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