Pancreas - Adverse Effects
Fluorinated and Fluoride Pesticides
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

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.

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 ]

Canada: Regulatory Note REG2003-12. Fluazinam. Pest Management Regulatory Agency. Health Canada. Ottawa. October 27, 2003.

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.

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.

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).
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.

-- 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.

-- 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.

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.

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).
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.

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.

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]

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.

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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