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.
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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
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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 ³3500 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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