See some background on the Pancreas
The Endocrine System:
Illustration by K. Born in Our Stolen Future
(1996)
by Theo Colborn, Dianne Dumanoski and JP Myers
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.
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 ]
Ref: TOXNET profile from Hazardous Substances
Data Base for DICHLOROFLUOROMETHANE.
http://www.fluoridealert.org/pesticides/dichlorofluoromethan.toxnet.htm
Fluazinam
- Fungicide
- CAS
No. 79622-59-6
-- In subchronic and
chronic toxicity studies, fluazinam targeted the following organs:
liver, lung, uterus, testes, pancreas,
thymus, thyroid, stomach, eyes and brain... Endocrine-related
effects included small and/or flaccid testes, testicular tubular
atrophy, pancreatic exocrine atrophy
and thymic hyperplasia.
--
Recommended ADI.
0.0011 mg/kg bw/d based on 2 year carcinogenicity in mice (1.1
mg/kg/d with 100- fold UF, three-fold SF for endocrine-related
effects (testicular atrophy, pancreatic
exocrine atrophy), and three-fold for lack of DNT). MOS
for other critical endpoint(s) White matter vacuolation/Neurotox
NOEL for white matter vacuolation was 10 mg/kg/d in chronic dog
study (equivalent to 0.02 mg/kg/d Impurity-5). MOS = 9100. Tumours
NOEL for tumours was 3.8 mg/kg bw/d in 2-year rat study. MOS =
3450. Developmental effects NOAEL for developmental effects was
7 mg/kg bw/d in developmental rabbit study. MOS = 6350
[ MOS = Margin of Safety
]
Ref:
Canada: Regulatory
Note REG2003-12. Fluazinam. Pest
Management Regulatory Agency. Health Canada. Ottawa. October 27,
2003.
http://www.fluorideaction.org/pesticides/fluazinam.canada.report2003.pdf
Combined chronic toxicity/carcinogenicity
rats. NOAEL = Males: 0.38 mg/kg/day; Females: 0.47 mg/kg/day LOAEL
= Males: 3.8 mg/kg/day; Females: 4.9 mg/ kg/day based on
liver toxicity in both sexes, pancreatic
exocrine atrophy in females and testicular
atrophy in males. Some
evidence of carcinogenicity (thyroid gland follicular cell tumors)
in male rats, but not in females.
Ref: Federal Register: April 18, 2002. Fluazinam;
Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/fluazinam.fr.apr.18.2002.htm
Chronic toxicity. Fluazinam
was not carcinogenic in rats. A NOAEL of 10 ppm (0.43 mg/kg/day)
of fluazinam was established based on the following effects at
1,000 and/or 100 ppm: lower food consumption and efficiency of
food utilization, slight anemia, elevated cholesterol, increased
liver weights, an increased number of macroscopic liver and testes
lesions and an increased incidence of microscopically observed
lung, liver, pancreas, lymph node
and testes lesions.
Ref: Federal Register: December 6, 2000
[Page 76253-76258]. Notice of Filing Pesticide Petitions to Establish
and to Extend Tolerances for Certain Pesticide Chemicals in or
on Food.
http://www.fluoridealert.org/pesticides/fluazinam.fr.december.2000.htm
Fluthiacet-methyl
-Herbicide - CAS No. 117337-19-6
Likely to
be Carcinogenic to Humans. Pancreatic
cell tumors (exocrine
adenomas, islet cell adenomas, and combined islet cell tumors);
Sprague-Dawley rats (M). Hepatocellular
tumors (adenomas and combined adenoma/carcinoma); CD-1
mice (M & F). CD-1 mice (M & F).
Ref: 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.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
-- Fluthiacet-methyl
is classified as a "likely to be a human
carcinogen" based on the presence of pancreatic
tumors (exocrine adenomas, islet cell adenomas and combined islet
cell adenomas + carcinomas) in male rats and liver
tumors (adenomas and combined adenomas + carcinomas) in male and
female mice.
Ref: US EPA. Pesticide Fact Sheet. Fluthiacet-methyl
Reason for Issuance: Conditional Registration Date Issued: April
1999.
http://www.epa.gov/opprd001/factsheets/fluthiacet.pdf
-- Carcinogenicity.
NOAEL in males = rats 2.1 mg/kg/day LOAEL in males = 130 mg/kg/day
NOAEL in females = 2.5 mg/kg/day LOAEL in females = 154 mg/kg/day.
In males there were decreased body weight, liver toxicity,
pancreatic toxicity and microcytic anemia. In females there
were liver toxicity, uterine toxicity and slight microcytic anemia.
In males only at 130 and 219 mg/kg/day there was respectively,
an increase in the trend toward pancreatic
exocrine adenomas and pancreatic islet cell adenomas.
Ref: Federal Register: December 21, 2001.
Fluthiacet-methyl; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/fluthiacet.m.fr.dec.21.2001.htm
PFOS - PFOA
- Insecticide, US EPA List 3 Inert
Adverse signs of toxicity
observed in Rhesus monkey studies included anorexia, emesis, diarrhea,
hypoactivity, prostration, convulsions, atrophy
of the salivary glands and the pancreas, marked decreases
in serum cholesterol, and lipid depletion in the adrenals. The
dose range for these effects was reported between 1.5-300 mg/kg/day.
No monkeys survived beyond 3 weeks into treatment at 10 mg/kg/day
or beyond 7 weeks into treatment at doses as low as 4.5 mg/kg/day.
Ref:
November 21, 2002 report:
Hazard Assessment of Perfluorooctane sulfonate
(PFOS) and its salts.
Organisation
for Economic Co-operation and Development. ENV/JM/RD(2002)17/FINAL.
http://www.fluorideaction.org/pesticides/pfos.final.report.nov.2002.pdf
In
the second study, Goldenthal et al. (1978a) administered rhesus
monkeys, 2/sex/group,
doses of 0, 0.5, 1.5 or 4.5 rng/kg/day PFOS (FC-95) in distilled
water by gavage for 90 days... All monkeys in the 4.5 mg/kg/day
group died or were sacrificed in extremis between week 5 and 7
of the study. Beginning on the first or second day of the study,
these monkeys exhibited signs of gastrointestinal tract toxicity
including anorexia, emesis, black stool and dehydration. All of
the monkeys had decreased activity and just prior to death showed
marked to severe rigidity, convulsions, generalized body trembling
and prostration... All the male and females
had marked diffuse lipid depletion in the adrenals. One
male and two females had moderate diffuse atrophy of the pancreatic
exocrine cells with decreased cell size and loss of zymogen granules.
Two males and one female had moderate diffuse atrophy of
the serous alveolar cells characterized by decreased cell size
and loss of cytoplasmic granules.
Ref:
Sulfornated Perfluorochemicals
in the Environment: Sources, Dispersion, Fate and Effects.
Prepared by 3M. March 1,2000.
Abstract: Ammonium
perfluorooctanoate is a potent synthetic surfactant used in industrial
applications. It rapidly dissociates in biologic media to perfluorooctanoate
[CF3(CF2)6CO2-], which is the anion of perfluorooctanoic acid
[PFOA, CF3(CF2)6COOH]. PFOA is a peroxisome
proliferator known to increase the incidence of hepatic, pancreas
and Leydig cell adenomas in rats. The
pancreas acinar cell adenomas may be the consequence of a mild
but sustained increase of cholecystokinin as a result of hepatic
cholestasis. Although no significant clinical hepatic toxicity
was observed, PFOA was reported to have modulated hepatic responses
to obesity and alcohol consumption among production workers. To
further assess these hypotheses, we examined medical surveillance
data of male workers involved in ammonium perfluorooctanoate production
in 1993 (n=111), 1995 (n=80) and 1997 (n=74). Serum PFOA was measured
by high-performance liquid chromatography mass spectrometry methods.
Plasma cholecystokinin was measured (only in 1997) by the use
of direct radioimmunoassay. Serum biochemical tests included hepatic
enzymes, cholesterol and lipoproteins. Serum PFOA levels, by year,
were: 1993 (mean 5.0 ppm, SD 12.2, median 1.1 ppm, range 0.0-80.0
ppm); 1995 (mean 6.8 ppm, SD 16.0, median 1.2 ppm, range 0.0-114.1
ppm); and 1997 (mean 6.4 ppm, SD 14.3, median 1.3 ppm, range 0.1-81.3
ppm). Cholecystokinin values (mean 28.5 pg/ml, SD 17.1, median
22.7 pg/ml, range 8.8-86.7 pg/ml) approximated the assay's reference
range (up to 80 pg/ml) for a 12 hour fast and were negatively,
not positively, associated with employees' serum PFOA levels.
Our findings continue to suggest there is no significant clinical
hepatic toxicity associated with PFOA levels as measured in this
workforce. Unlike a previously reported observation, PFOA did
not appear to modulate hepatic responses to either obesity or
alcohol consumption. Limitations of these findings include:
1) the cross-sectional design as only 17 subjects were common
for the three surveillance years;
2) the voluntary participation that ranged between 50 and 70 percent;
and
3) the few subjects with serum levels > or = 10 ppm.
Ref:
2000. Drug Chem Toxicol Nov;23(4):603-20. Plasma
cholecystokinin and hepatic enzymes, cholesterol and lipoproteins
in ammonium perfluorooctanoate production workers; by Olsen
GW, Burris JM, Burlew MM, Mandel JH.
Medical Department, 3M
Company, St. Paul, MN 55144-1000,
USA.
Prodiamine
- Herbicide - CAS No. 29091-21-2
Group
C -- Possible Human Carcinogen. Thyroid
follicular
cell neoplasia (M & F); Pancreatic adenomas
(F) in Sprague-Dawley rats. Fibrosarcomas;
CD-1 mice (M).
Ref: 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.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
Sodium
fluoride - Insecticide,
Wood preservative, US EPA List 4B Inert - CAS No. 7681-49-4
Abstract: The aim of this work was to examine the effect of fluoride
ions on antioxidative enzyme activity in the pancreas of rats
exposed during 4 months to NaF in drinking water. The study was
carried out in 30 four-week-old male Wistar FL rats, that were
randomly assigned to three equal groups and given distilled water
ad libitum for three weeks. Subsequently, two examined groups
of animals were exposed to NaF in drinking water: group 1 (10
rats) at 50 mg F(-)/L (2.63 mmol/L), group 2 (10 rats) at 100
mg F(-)/L (5.26 mmol/L). The control group (10 rats) received
distilled water. After 4 months the animals were anesthetized
with ether prior to collection of pancreas and cardiac blood.
Serum concentrations of glucose and fluoride, as well as activities
of the cytoplasmic (CuZn-SOD) and the mitochondrial (Mn-SOD) superoxide
dismutase, glutathione peroxidase (GSH-Px) and concentrations
of malondialdehyde (MDA) in the homogenized pancreas were measured.
The activity of CuZn-SOD was reduced by 50% and a tendency to
lower activities of Mn-SOD was observed. No changes were noted
in the activity of GSH-Px or concentrations of MDA. We conclude
that:
1) the fluoride caused hyperglycemia in rats in this study is
not accompanied by an activation of the free radical production
in the pancreas;
2) the hyperglycemia in the exposed rats cannot be attributed
to pancreatic damage caused by fluoride ions (the cause in this
case appears to be extrapancreatic);
3) the inhibition of pancreatic CuZn-SOD
is probably due to the direct action of fluoride on the enzyme.
Ref: J Trace Elem Med Biol 2003;17(1):57-60.
Activity
of pancreatic antioxidative enzymes and malondialdehyde concentrations
in rats with hyperglycemia caused by fluoride intoxication.
by Chlubek D et al.
Abstract: Influence of fluoride on exocrine pancreas cells was
examined morphologically with traditional and prolonged osmium
fixation techniques for electron microscopy in the enamel fluorosis
model rats injected subcutaneously twice a day with 20 mg/kg body
weight of sodium fluoride. Although the rough endoplasmic reticulum
(rER) of exocrine pancreas cells in control rats was laminated
and oriented parallel to the circumference of the nucleus, the
rER of the cells in NaF-treated rats was dilated, disrupted the
laminated arrangement, and changed to the globular-shape rER.
Many intracisternal granules were formed in these globular-shape
rER of the cells exposed to fluoride. Lots of autophagosomes were
also seen in the exocrine cells with NaF treatment. The autophagosomes
were limited with a double or multiple membranes, and contained
cytoplasmic organelles and/or the intracisternal granules. The
outer and inner leaflets of double membranes of the autophagosomes
were usually separated by a distinct electron-lucent area. In
prolonged osmium fixation, the area between the double membranes
of the autophagosome was filled with osmiun reaction deposits.
Many autophagosomes were encircled with the single or multiple
osmiophilic layers. In some cases, the osmium positive saccules
also surrounded the free surface of the globular-shape rER containing
intracisternal granules. These findings
indicate that fluoride disrupts the export of zymogens from the
rER, resulting in formation of intracisternal granules and autophagosomes,
and that the osmiophilic saccules participate in sequestration
of cytoplasmic organelles in forming autophagosomes.
Ref: Arch Toxicol 2000 Feb;73(12):611-7.
Fluoride-induced ultrastructural changes in exocrine pancreas
cells of rats: fluoride disrupts the export of zymogens from the
rough endoplasmic reticulum (rER). by Matsuo S et al.
Teflubenzuron
- Insecticide, Insect growth regulator
- CAS No. 83121-18-0
-- In a 120-week long-term
toxicity/carcinogenicity study, rats were fed diets containing
0, 20, 100 or 500 mg/kg feed, equal to 0, 1, 4.8 or 24.8 mg/kg
bw/day in males and 0, 1.2, 5.9 and 29.9 mg/kg bw/day in females...
Histopathological examination indicated an increased incidence
of mesenteric lymph node haemangiomas in males in the high dose
group (17%) in comparison with rats in concurrent controls (2%),
but not when compared to the incidence in historical controls.
A significantly increased incidence of pancreatic
exocine carcinomas in male rats in the high dose group
(4.3%), compared to concurrent controls (0 out of 50) and historical
control groups (1.4% or 1 out of 69), was based on a low number
of affected rats (2 out of 47) and was therefore not considered
to be treatment related.
Ref:
January 1999 - Summary Report. Committee for Veterinary Medicinal
Products. The European Agency for the Evaluation of Medicinal
Products.
http://www.fluoridealert.org/pesticides/teflubenzuron.review.1999.pdf
Tembotrione - Herbicide - CAS No. 335104-84-2
• Certain changes in multiple organs seen in the subchronic, chronic, dermal, and reproduction studies (e.g., microscopic changes in the thyroid gland, adrenal gland, and pancreas; increased number of corpora lutea in the ovary, and delayed preputial separation) may be due to various mechanisms including possible liver-pituitary-thyroid homeostatic disruption or inhibition of steroid synthesis (Page 6)... When additional appropriate screening and/or testing protocols being considered under the Agency’s EDSP have been developed, tembotrione may be subjected to further screening and/or testing to better characterize effects related to endocrine disruption (page 29).
• Thyroid gland toxicity was observed in the 21/28-day dermal toxicity study in the rat and chronic oral toxicity study in the dog. Dermal exposure (21/28-day study) resulted in colloid alteration and hypertrophic follicular epithelium in the thyroid gland in the rat. Also observed were degenerative changes in the pancreas, increased proteinacious material in the Ratche pouch in the pituitary gland and basophilic tubules in the kidneys. Pigmentation of the thyroid gland along with hematological changes and microscopic changes in the sciatic nerve were observed in the dog.
• In a combined chronic/carcinogenicity study (MRID 46695708) Wistar male rats/dose in the diet at dose levels of 0, 1, 20, 200 or 800 ppm (equivalent to 0, 0.04, 0.79, 8.3 or 31.7 mg/kg bw/day) in the diet for 104 weeks. In the pancreas, the incidence of minimal to moderate acinar atrophy/fibrosis was significantly increased (p≤0.01) in the 200 and 800 ppm groups (63% and 67%, respectively), when compared to controls (35%). Pancreatic acinar atrophy/fibrosis generally is a focal or lobular atrophy (dedifferentiation of acinar cells and an increase in small duct-like structures), sometimes associated with a relative increase in interstitial collagen and a small number of inflammatory cells, but in the 200 and 800 ppm dose groups this lesion was more diffuse in distribution (page 73).
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.
Trifloxystrobin
- Fungicide - CAS No. 141517-21-7
-- Subchronic
toxicity. In subchronic studies, several mortality related
changes were reported for the top dose in dogs (500 mg/kg) and
rats (800 mg/kg). At these dose levels, excessive toxicity has
resulted in body weight loss and mortality with the associated
and non-specific changes in several organs (such as
atrophy in the thymus, pancreas,
bone marrow, lymph node, and spleen) which are not considered
specific target organs for the test compound. In the dog, specific
effects were limited to hepatocellular hypertrophy
at 150 mg/kg and hyperplasia of the epithelium of the gall bladder
at 500 mg/kg. Target organ effects in the rat were noted as hepatocellular
hypertrophy (200 mg/kg) and the related liver weight increase
(50 mg/kg). In the mouse, target organ effects included single
cell necrosis (300 mg/kg) and hypertrophy (1,050 mg/ kg) in the
liver and extramedullary hematopoiesis (300 mg/ kg) and hemosiderosis
in the spleen (1,050 mg/kg). In general, definitive target organ
toxicity, mostly in the liver, was seen at high feeding levels
of over 100 mg/kg for an extended treatment period. At the lowest
observed adverse effect level (LOAEL), no serious toxicity was
observed other than mostly non-specific effects including a reduction
in body weight and food consumption or liver hypertrophy.
Ref: Federal Register. November 14, 2001.
[PF-1048; FRL-6806-6]
http://www.fluoridealert.org/pesticides/trifloxystrobin.fr.nov14.01.htm
Short
term toxicity.
Target / critical effect: Decreased
bodyweight & food consumption. Liver: increased weight, hepatocellular
hypertrophy and necrosis. Kidney: increased weight and acute tubular
lesions. Pancreas: atrophy. Lowest
relevant oral NOAEL / NOEL: 90-day rat: 100 ppm (6.4 mg/kg bw/day).
Lowest relevant dermal NOAEL / NOEL: 28-day rat: 100 mg/kg bw/day.
Lowest relevant inhalation NOAEL / NOEL: No study - not required
Ref:
Review report for the active substance trifloxystrobin. Trifloxystrobin.
SANCO/4339/2000-Final. 7 April 2003. Finalised in the [European
Commission] Standing Committee on the Food Chain and Animal Health
at its meeting on 15 April 2003 in view of the inclusion of trifloxystrobin
in Annex I of Directive 91/414/EEC.
http://www.fluorideaction.org/pesticides/trifloxystrobin.eu.april.03.pdf
Triphenyltin
fluoride - Antifoulant,
Algaecide, Herbicide - CAS No. 379-52-2
Pub
Med abstract: ...Recently we found that a single oral administration
of triphenyltin fluoride to rabbits induces transient diabetes
and diabetic lipemia by inhibiting insulin
secretion from morphologically normal pancreatic B-cells...
Ref: [Recent
progress in the study of analytical methods, toxicity, metabolism
and health effects of organotin compounds]
by Wada O, Manabe S, Iwai H, Arakawa Y. Sangyo Igaku 1982 Jan;24(1):24-54
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