Leukemia - Adverse Effects
Fluorinated and Fluoride Pesticides

Leukemia is a malignant disease (cancer) of the bone marrow and blood. It is characterized by the uncontrolled accumulation of blood cells. Leukemia is divided into four categories: myelogenous or lymphocytic, each of which can be acute or chronic. The terms myelogenous or lymphocytic denote the cell type involved. Thus, the four major types of leukemia are:

• Acute Lymphocytic Leukemia
• Chronic Lymphocytic Leukemia
• Acute Myelogenous Leukemia
• Chronic Myelogenous Leukemia

Acute leukemia is a rapidly progressing disease that results in the accumulation of immature, functionless cells in the marrow and blood. The marrow often can no longer produce enough normal red blood cells, white blood cells and platelets. Anemia, a deficiency of red cells, develops in virtually all leukemia patients. The lack of normal white cells impairs the body's ability to fight infections. A shortage of platelets results in bruising and easy bleeding. Chronic leukemia progresses more slowly and allows greater numbers of more mature, functional cells to be made.

New Cases
Among an estimated 30,600 new cases of leukemia in the United States this year, about equal proportions are acute leukemia and chronic types. Most cases occur in older adults; more than half of all cases occur after age 64. Leukemia is expected to strike 8 times as many adults as children in 2003. (About 27,815 adults compared with 3,441 children, ages 0-19). About 30 percent of cancers in children ages 0-14 years are leukemia. The most common form of leukemia among children under 19 years of age is Acute Lymphocytic Leukemia (ALL).
The most common types of leukemia in adults are acute myelogenous leukemia (AML), with an estimated 10,500 new cases annually, and chronic lymphocytic leukemia (CLL), with some 7,300 new cases each year. Chronic myelogenous leukemia (CML) affects about 4,300 persons each year. Acute lymphocytic leukemia (ALL) will account for about 3,600 cases this year. Other unclassified forms of leukemia account for the 4,900 remaining cases.

Incidence by Gender
Incidence rates for all types of leukemia are higher among males than among females. In 2003, males are expected to account for more than 58 percent of the cases of leukemia. (Note: Incidence rates are the number of new cases in a given year not counting the pre-existing cases. The incidence rates are usually presented as a specific number per 100,000 population.)

Ref: http://www.leukemia.org/all_page?item_id=9346

The use of high doses increases the likelihood that potentially significant toxic effects will be identified. Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans. From a conservative risk assessment perspective however, adverse findings in animal species are assumed to represent potential effects in humans, unless convincing evidence of species specificity is available.

-- Food and Agricultural Organization of the United Nations

Note: This is not an exhaustive list.
When time allows more information will be added.

Arsenic trifluoride - Wood Preservative - CAS No. 7784-35-2

HEMATOLOGIC. ACUTE EXPOSURE. Acute hemolysis and anemia may occur after acute poisoning. Pancytopenia, aplastic anemia, or leukemia may occur following chronic exposure. Bone marrow
depression can occur.
Ref: TOXNET profile from Hazardous Substances Data Bank for ARSENIC TRIFLUORIDE
CASRN: 7784-35-2.


Dichlorodifluoromethane - Insecticide, Fungicide Propellant, EPA List 2 Inert - CAS No. 75-71-8

-- Dichlorodifluoromethane ... /was/ tested by inhalation on Sprague-Dawley rats and Swiss mice. The animals were exposed for 4 hr a day, 5 days a week; rats were exposed for 104 weeks, and mice were exposed for 78 weeks. Animals were observed until spontaneous death. Exposure of rats to dichlorodifluoromethane resulted in no noticeable differences in the incidence of total benign and malignant tumors, and of the most frequently expected or rate of tumors. Exposure of mice to dichlorodifluoromethane resulted in a higher number of total tumors in males and females which was dose related in males, pulmonary adenomas in males and females at 5000 ppm, and leukemias in males at 5000 and 1000 ppm and in females at 1000 ppm. [Maltoni C et al; Annals of the New York Academy of Sciences 534: 261-82 (1988)]
Ref: TOXNET profile from Hazardous Substances Data Bank for Dichlorodifluoromethane.


Dichlorofluoromethane (CFC-21) - Propellant, EPA List 2 Inert - CAS No. 75-43-4

TSCA Test Submissions: A subchronic inhalation toxicity study was conducted with groups of male (35) and female (35) albino rats (strain not reported) receiving whole body exposure to dichloromonofluoromethane at a nominal concentration of 0, 50, 150 or 500ppm in a dynamic air flow chamber for 6 hours per day, five days per week for approximately 90 days. On day 45 and day 90, 5 animals per sex and 20 animals per sex, respectively were sacrificed. The remaining animals were observed for an additional 30 days and then sacrificed. Four high dose males were found dead during the exposure period and one female and six males from the high dose group were found dead during the recovery period. High dose rats were observed to have statistically significant (p < 0.01) lower body weights than controls during the exposure period, but were comparable after the 30 day recovery period. Hematology, clinical chemistry and urine analysis values were similar between all dosed animals and control animals, with the exception of a slightly higher total blood leukocytes counts and elevated mean SAP and SGPT values for high dose animals at approximately 45, 90 and 120 days. A dose related increase in urine fluoride levels was also observed. Histopathology evaluation of treated animals revealed portal cirrhosis of the liver, interstitial edema of the pancreas and degeneration of the seminiferous epithelium. Three cases of leukemia were observed in high dose male rats. [Industrial Bio-Test Laboratories; Subacute Inhalation Toxicity Study with Genetron 21 in Albino Rats, (1979), EPA Document No. FYI-OTS-0779-0045, Fiche No. OTS0000045-0 ]
[Note from FAN: seminiferous epithelium = the epithelium lining the convoluted tubules of the testis where spermatogenesis and spermiogenesis occur.]
Ref: TOXNET profile from Hazardous Substances Data Base for DICHLOROFLUOROMETHANE.


Fluometuron - Herbicide - CAS No. 2164-17-2

EPA has determined that there is not enough evidence that fluometuron causes cancer in animals to justify its classification as a carcinogen. Fluometuron is not classified as a carcinogen by the EPA (20). An increased incidence of liver-cell tumors in male mice was noted in a study of rats and mice. In the same study, no carcinogenic effects were observed in female mice or in rats of either sex (18). Mice that were given oral doses of 87 mg/kg for two years had evidence of liver tumors and leukemia, a condition characterized by uncontrolled growth in the number of white blood cells in the blood stream (National Institute for Occupational Safety and Health (NIOSH). 1986. Registry of toxic effects of chemical substances (RTECS). Cincinnati, OH: NIOSH.)
Ref: 1994 Pesticide Information Profile. EXTOXNET.

Penoxsulam - Herbicide - CAS No. 219714-96-2

Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential. Mononuclear cell leukemia in Male Fischer 344 rats. Although dosing in male mice was not considered to be adequate, an additional mouse carcinogenicity study was not required.
April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs. From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.

-- Carcinogenicity: Evidence of carcinogenicity in male rats based on possibly treatment related increase incidence of Large Granular Lymphocyte (LGL) Leukemia at 5, 50, & 250 mg/kg/day. Also increase severity at 250 mg/kg/day. Female rats - negative for carcinogenicity, but dosing was only marginally adequate.
-- Carcinogenicity-mice: In males, negative for carcinogenicity at doses tested. Dosing inadequate.
-- The Agency (US EPA) has classified penoxsulam as Suggestive Evidence of Carcinogenicity, But not sufficient to assess human carcinogenic potential and, therefore, quantification of human cancer risk is not required. The weight-of-the-evidence for this classification is as follows: a. Evidence of carcinogenicity (mononuclear cell leukemia (MNCL)) was seen in one sex (males) of one species (rat).b. There was an increased incidence of MNCL at all dose levels with all incidences exceeding the laboratory historical control, however, the dose-response was flat over a wide range of doses. c. Although MNCL is recognized as a common neoplasm in Fischer rats, the mechanism of producing MNCL is not completely understood. Therefore, the significance of MNCL and its biological relevance for human cancer risk remains uncertain and cannot be discounted ...
Ref: September 24, 2004. Penoxsulam Pesticide tolerance. Final Rule. Federal Register.

-- Chronic toxicity. Chronic exposure in the dog indicated that the renal effects were not exacerbated with long-term exposure. Following long-term exposure in rats, the kidneys and urinary bladder were the primary target organs. Histologic changes seen at the end of 2 years of exposure consisted of inflammation and hyperplasia of the renal pelvic transitional epithelium, crystal deposition in the kidneys and urinary bladder, and hyperplasia of the mucosa of the urinary bladder. In the mouse, the liver was the primary target organ, and histologic changes consisted of hepatocellular hypertrophy. There were no treatment-related increases in tumors in either rats or mice. The incidence of mononuclear cell leukemia (Fischer rat leukemia) was increased in all groups of treated male rats compared to the concurrent controls. However, the incidences in the treated groups were identical across a 50-fold increase in dosage, and well within the range of control values reported in the literature.
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.


In a carcinogenicity study in rats, male and female rats were given penoxsulam in the diet for two years at dose levels of 0, 5, 50 or 250 mg/kg/day. In this study, there was a statistically significant increased incidence of malignant large granular lymphocyte (LGL) leukemia in each of the male treatment groups. The incidence was 24%, 60%, 58% and 60% in the control, low, mid and high dose level groups respectively. There was no dose response with all treated male groups having an approximately 2.5 fold increase over control animals. The incidence in the male treatment groups exceeded the conducting laboratory‘s historical control mean (28.5%) and range (16-40%), but fell within the National Toxicology Program (NTP) historical control data base of mean (50.5%) and range (32-74 %). There was also an increased severity (Stage 3) of LGL leukemia in all the treated male groups compared to the control group. There was no increase in incidence or severity of LGL leukemia for the treated female rats in this study. The dose levels in this study were considered to be adequate in male rats and marginally adequate in female rats to assess the carcinogenicity of penoxsulam.
Reference: September 2004. US EPA Fact Sheet on Penoxsulam. Page 4.

Trichlorofluoromethane -Insecticide, Fungicide, Propellant, EPA List 2 Inert - CAS No. 75-69-4

-- Trichlorofluoromethane ... /was/ tested by inhalation on Sprague-Dawley rats and Swiss mice. The animals were exposed for 4 hr a day, 5 days a week; rats were exposed for 104 weeks, and mice were exposed for 78 weeks. Animals were observed until spontaneous death. Trichlorofluoromethane exposure to rats caused no carcinogenic effects. Trichlorofluoromethane exposure to mice caused increased numbers of total tumors in females which was dose related, mammary tumors in females at 5000 ppm, lung adenomas and leukemias in females, both dose related. [Maltoni C et al; Annals of the New York Academy of Sciences 534: 261-82 (1988)]
Ref: Hazardous Substances Data Base for TRICHLOROFLUOROMETHANE.

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