Amyloidosis - Adverse Effects
Fluorinated and Fluoride Pesticides
 
 

A little background on Amyloidosis
-- Also see http://amyloidosis.org/whatisit.asp

1. PRIMARY AMYLOIDOSIS is a plasma cell disorder which originates in the bone marrow and is usually treated with chemotherapy. It is the most common type of amyloidosis in the United States, with estimates of up to 2000 cases diagnosed each year, and occasionally occurs with multiple myeloma. The deposits in this type of the disease are made up of immunoglobulin light chain proteins which may be deposited in any bodily tissues or organs. The disease results when enough amyloid protein builds up in one or more organs to cause the organ(s) to malfunction. The heart, kidneys, nervous system and gastrointestinal tract are most often affected.

Normally, bone marrow makes protective antibodies, which are proteins that protect against infection and disease. After they have served their function, these antibodies are broken down and recycled in the body. With amyloidosis, cells in the bone marrow produce antibodies that cannot be broken down. These antibodies then begin to build up in the bloodstream. Ultimately, they leave the bloodstream and can deposit in the tissues or organs as amyloid.

2. SECONDARY AMYLOIDOSIS is caused by a chronic infection or inflammatory disease such as rheumatoid arthritis, familial Mediterranean fever, osteomyelitis, or granulomatous ileitis. The deposits in this type of the disease are made up of a protein called the AA protein. Medical or surgical treatment of the underlying chronic infection or inflammatory disease can slow or stop the progression of this type of amyloid.

3. FAMILIAL (or HEREDITARY) AMYLOIDOSIS is the only type of amyloidosis that is inherited. It is a rare form of the disease which is found in families of nearly every ethnic background. The deposits in this type are most commonly made up of the transthyretin protein which is manufactured in the liver. It is a mutation of such a protein that causes this form of amyloidosis.

4. OTHER TYPES OF AMYLOIDOSIS include localized amyloid, b2 micro globulin amyloid, and Alzheimer's disease. Localized types of amyloidosis are associated with hormone proteins, aging, or specific areas of the body, and have not been found to have systemic implications. The type of amyloidosis which is due to the b2 micro globulin protein may affect people who have been on dialysis for a significant length of time. In Alzheimer's disease, the amyloid protein in the brain is called the b-amyloid protein.

-- Also see: Brown P. Transmissible human spongiform encephalopathy (infections cerebral amyloidosis): Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome and kuru. In CaIne D B, ed, Neurodegenerative disease. Philadelphia: WB Saunders, 1994:839-76.


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.


Flurtamone - Herbicide - CAS No. 96525-23-4

-- Two-year dietary study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose) were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone (91.9% purity) for at least 78 weeks... The mean intake of flurtamone for males and females was estimated to be 4.5, 45, 525 and 1050 mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After 78 weeks of treatment, the mortality rate for the 7000 ppm female mice was significantly higher than controls and a significant negative survival trend was found in both sexes. The test laboratory pathologist considered systemic amyloidosis to be the major cause of death (Table 5.24) [page 102]. Gross necropsy revealed an increased incidence of enlarged livers and liver masses at dose levels 3500 and of irregular shaped kidneys at 7000 ppm. Significant increases in mean liver weight (absolute and relative) were observed in 3500 and 7000 ppm animals (not statistically significant in 3500 ppm males) at both the interim and terminal sacrifices (Table 5.26). Significant decreases in mean absolute kidney weights were observed in males at 7000 ppm at the interim and terminal sacrifices [page 103]. Microscopic examinations revealed an increased incidence of systemic amyloidosis (most severe in the kidneys) in the 3500 and 7000 ppm animals and the 300 ppm females that died or were sacrificed in extremis. The incidence and severity of renal amyloidosis is given in Table 5.27 [page 104]... Based on the incidence and severity of renal amyloidosis associated with early death in females at 300 ppm, the test laboratory proposed a NOEL for non-neoplastic lesions of 30 ppm (equivalent to approximately 4 mg/kg/day) for this study. The NOEL for neoplastic lesions in mice was determined to be 300 ppm (equivalent to approximately 45 mg/kg/day). In the opinion of the applicant [Rhone-Poulenc Agriculture Ltd], the observed amyloidosis in the above study was not a treatment-related effect of flurtamone administration. The incidences of amyloidosis in this study were re-analysed by an independent pathologist but the histopathological slides were not re-examined. It should be noted that systemic amyloidosis is a common age-related condition in CD-1 mice with a tendency to be more frequent as a cause of death in females than in males and the incidence varies widely within laboratories and between laboratories [page 105]... [page 108].

Flurtamone: Table 5.27 The incidence and severity of renal amyloidosis in unscheduled deaths [page 104]
Dose
Males
Females
(ppm)
Incidence
Mean grade
Incidence
Mean grade
0
1/10 (10%)
0.6
2/7 (29%)
0.9
30
3/5 (60%)
2.4
1/8 (14%)
0.9
300
3/11 (30%)
1.2
7/13 (54%)
2.0
3500
10/13 (77%)
2.9
7/12 (64%)
2.8
7000
10/13 (77%)
2.8
9/19 (47%)
2.1

Flurtamone: Table 5.24 Survival and incidence of amyloidosis as a cause of death [page 103]
Dose
Males
Females
(ppm)
Survival
(%)
Amyloid
(COD*)
Survival
(%)
Amyloid
(COD*)
0
86.8
0/50 (0%)
88.1
1/50 (2%)
30
90.0
3/50 (6%)
87.8
0/50 (0%)
300
78.8
3/50 (6%)
75.5
6/50 (12%)
3500
74.0
8/50 (16%)
77.4
7/50 (14%)
7000
74.5
7/50 (14%)
66.2
9/50 (18%)
COD = cause of death

Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at: http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Hydramethylnon - Insecticide - CAS No. 67485-29-4

In a carcinogenicity study, MRID 00101563, groups of 50 male and 50 female Charles River CD-1 mice received diets containing hydramethylnon at dose levels of 0, 25, 50, 100, or 200 ppm (0, 3.57, 6.93, 14.2, or 28.6 mg/kg/day in males, and 0, 4.45, 6.87, 17.3, or 33.1 mg/kg/day in females, based on food consumption) for 18 months. The 200 ppm males and females were sacrificed after 55 weeks because of high mortality. Survival after 18 months at the 50 and 100 ppm doses was 72% and 46% in males, and 66% and 46% in females (compared to control survival of 86% in males and 76% in females)... Dose-related amyloidosis was seen in the kidneys of the 50 and 100 ppm females.
Ref: US EPA. Reregistration Eligibility Decision (RED) Hydramethylnon. EPA 738-R-98-023. December 1998.
http://www.fluoridealert.org/pesticides/hydramethylnon.red.1998.pdf

18-Month Feeding (oncogenic) - mouse: Systemic NOEL=25 ppm (2.75 mg/kg/day); Systemic LEL=50 ppm (3.75 mg/kg/day) (increased testicular lesions, decreased body weight gain, increased renal amyloidosis); core grade minimum (American Cyanamid, 1982d).
Ref: US EPA IRIS for Amdro (CASRN
67485-29-4).
http://www.epa.gov/iris/subst/0207.htm

Chronic toxicity... In an 18-month cancer assay, hydramethylnon at about 3.8 mg/kg/day was associated with amyloidosis, a syndrome in which abnormal protein deposition in the kidney fitration unit (glomerulus) results in damage [13].
Ref: E X T O X N E T Extension Toxicology Network Pesticide Information Profiles for Hydramethylnon.
http://ace.ace.orst.edu/info/extoxnet/pips/hydramet.htm

Isoxaflutole - Herbicide - CAS No. 141112-29-0

An oncogenicity study in mice administered 0, 25, 500 and 7,000 ppm with a NOEL of 25 ppm based on a slight effect on liver weight and body weight gain at the LEL of 500 ppm. An increased incidence of hepatocellular adenomas and carcinomas was observed at 7,000 ppm in both sexes. Increased liver weight, non-neoplastic cellular changes in the liver, and amyloidosis in the duodenum, ileum, jejunum, kidneys, heart ventricle, mesenteric lymph node, and thyroid were also observed at 7,000 ppm.
Ref: Federal Register: February 26, 1997 (Volume 62, Number 38)] [Notices] [Page 8737-8740]. Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing.

http://www.epa.gov/EPA-PEST/1997/February/Day-26/p4628.htm

Sulfuryl fluoride - Fumigant, Insecticide - CAS No. 2699-79-8

ONCOGENICITY, MOUSE **50223-028 125636 "Sulfuryl Fluoride: 18-Month Inhalation Oncogenicity Study in CD-1 Mice", (J. F. Quast, G. J. Bradley and K. D. Nitschke, Dow Chemical Co., Toxicology Research Laboratory, Lab Project Study ID K-016399-039, 8/19/93). Sulfuryl fluoride, 99.8% purity, was administered via inhalation at concentrations of 0, 5, 20, or 80 ppm to 50 CD-1 mice/sex/group for 6 hours/day, 5 days/week for 18 months. Ten additional mice/sex per dose level were included for sacrifice at 12 months. NOEL = 20 ppm. Primary concern was increased mortality in females (mainly due to increased incidence of severe degree of bilateral amyloidosis in glomeruli). Possibly treatment-related findings in males were food impaction in esophagus and inflammation and/or abscesses in the head and/or oral cavity at 80 ppm. Lesser changes at 80 ppm included very slight vacuolation of brain, particularly of cerebral external capsule (M and F), and very slight hypertrophy of thyroid epithelial cells (especially in males). This study is considered to indicate a "possible adverse effect", based on the exacerbation of geriatric renal disease in high dose females. Considering how high the NOEL and LEL of this study are to levels which cannot be tolerated in acute and subacute toxicity exposure, this flagging of a "possible adverse effect" should not be taken to indicate unusual concern. No oncogenicity effects. Acceptable. Kishiyama and Aldous, Sept. 14, 1994.
Ref: SUMMARY OF TOXICOLOGY DATA SULFURYL FLUORIDE. Revised 11/17/98. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

http://www.fluorideaction.org/pesticides/sulfuryl.fluoride.tox.data.pdf

Tetraconazole -Fungicide - CAS No. 112281-77-3

Chronic & Carcinogenicity Studies. Findings in other organs included enlarged cervical lymph nodes at 800 and 1250 ppm, prominent alveolar macrophages in the lungs of males at 1250 ppm and females of all treated groups, pneumonitis in females at 800 and 1250 ppm, involution in the thymus of males at 1250 ppm, and amyloidosis in various organs of mainly males at 800 and 1250 ppm. ...Dogs received 0, 22.5, 90 or 360 ppm of tetraconazole in the diet for 1 year. Histopathology detected apparent hepatocyte enlargement, eosinophilic inclusions in hepatocytes, centrilobular hepatocyte rarefaction, or centrilobular fat in the liver at 90 and 360 ppm, and cortical tubular hypertrophy and apoptotic bodies in the kidneys at 360 and/or 90 ppm. The NOEL was 22.5 ppm (0.7 mg/kg bw/day). (page 5)
Ref: August 2005 - Evaluation of Tetraconazole in the product Domark 40ME Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf

Thiazopyr - Herbicide - CAS No. 117718-60-2

-- A mouse carcinogenicity study at doses of 0, 0.17, 1.6, 16.9, 66.3 or 128.4 mg/kg/day (males) and 0,0.24, 2.6, 26.8, 108.1 or 215.9 mg/kg/day (female) with a systemic NOEL of 0.1 mg/kg/day. The effects were hepatocellular hypertropy and amyloid deposition. At 66.3 mg/kg/day the same lesions plus increased liver weights, random and periportal hepatocellular vacuolation were observed. At 128.4 mg/kg/day the same lesions plus distended abdonen, slight increase in ALP, SGOT and SGPT, abnormal coloration and enlargement of liver, decrease in absolute and relative spleen weights, increase in absolute and relative kidney weights, increase in eosinophilia in hepatocytes, kidney nephropathy and lymphocytic hyperplasia of the nesenteric lymph nodes were observed. There was no evidence of oncoenicity at any dose level.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.

http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

 
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