JPC SYSTEMIC PATHOLOGY
SIGNALMENT (JPC 1947713): A male Sprague-Dawley rat
HISTORY: This rat was on a chronic 2-year oral toxicity study. Malocclusion and dental fractures were common in treated animals. The surfaces of the incisors were white, thickened or pitted. Frequently, the nasal, maxillary, frontal and parietal bones of treated rats were white, thickened, and rough compared to those of control animals. The changes were bilaterally symmetrical.
HISTOPATHOLOGIC DESCRIPTION: Cranium, cross section through maxillary sinuses: Bilaterally, teeth contain disorganized cuboidal to columnar ameloblasts that occasionally pile up 4-5 layers deep and line an enamel layer that has scalloped borders, increased clear space separating the enamel matrix, and numerous variably sized, up to 10um diameter basophilic globules. There are multifocal areas with thinning of ameloblasts and subsequent thinning of enamel. The predentin and dentin layers are irregular, thickened 2‑3 times normal, and contain numerous variably sized and coalescing, up to 20um diameter, basophilic globules. The odontoblastic layer is thickened up to 2 times normal by increased numbers of vacuolated odontoblasts. Ameloblasts and odontoblasts occasionally contain similar basophilic globules. Diffusely, trabecular bone of the maxilla and cranium is mildly thickened (osteosclerosis) and the matrix is disorganized with numerous basophilic resting and reversal lines, reminiscent of woven bone, and the bone has scalloped borders lined by osteoblasts, , and there are numerous basophilic globules within the tooth matrix (similar to the tooth matrix). The medullary spaces are small and contain increased fibrous connective tissue. Multifocally, within the subepithelial connective tissue of the floor of the maxillary sinuses are small aggregates of lymphocytes and plasma cells that form follicles.
- Teeth, bilateral: Dysplasia, ameloblastic and odontoblastic, diffuse, moderate, with enamel loss and malformation, dentin malformation, and basophilic globular material within ameloblasts, odontoblasts, dentin and enamel, Sprague-Dawley rat, rodent.
- Cranium: Osteosclerosis, diffuse, mild, with intratrabecular basophilic globular material.
ETIOLOGIC DIAGNOSIS: Dental fluorosis and osteofluorosis
CONDITION: Fluoride toxicity (fluorosis)
- Fluorosis is chronic fluoride toxicity which most commonly occurs in herbivores; cattle are more susceptible than sheep and horses
- Ameloblasts and odontoblasts are highly sensitive to fluorine
- Principal changes in teeth include “chalky” areas, “mottling”, excessive attrition, and hypoplastic pitting of the enamel
- Sources of fluorine include pastures or forage contaminated by airborne residues from aluminum manufacturers, volcanic ash, phosphate refineries, and similar industrial installations; feed supplements and mineral mixtures with excessive fluoride; drinking well water containing soluble fluorides > 10 ppm or more; dust from volcanic eruptions also contains abundant fluorides
- Fluoride toxicity is enhanced by poor nutrition, and alleviated somewhat by high dietary intakes of calcium and aluminum
- Fluorine is incorporated into bone matrix during mineralization and will therefore mostly affect young animals at sites of active formation; however, in older animals, fluorine deposition can occur during remodeling; exposure of cattle after 3 years of age typically results in osteofluorosis and not dental flourosis
- Acute toxicosis results from accidental massive ingestion of fluoride compounds, inhalation of gas anesthetics (methoxyflurane or halothane), and ingestion of rodenticides (dogs/cats) or anti-parasitic compounds (swine/poultry)
- Gastrointestinal irritation (hydrofluoric acid)
- Tetany and hyperesthesia (altered membrane ion exchange)
- Formation of calcium fluoride depletes serum calcium > inhibition of blood coagulation
- Chronic toxicosis results from ingestion of small amounts of fluoride compounds over long periods
- Fluoride is removed rapidly from the blood by renal excretion and deposited in bones and teeth; a small amount is deposited in soft tissues
- Ingestion of toxic concentrations during odontogenesis (6 to 36 months of age) results in the incorporation of fluoride into the enamel and dentin
- Fluoride disrupts ameloblasts > irregular enamel matrix, rate of formation, and rate of mineralization > outer layer of enamel is hypomineralized
- Odontoblasts are also damaged, yet retain the ability to produce dentin after a tooth is fully formed > production of secondary dentin in an attempt to compensate for rapid tooth wear
- Oxidation of exposed dentin results in dark discoloration
- Bone: Mechanism is unknown
- Can lead to osteosclerosis, osteoporosis, hyperostosis, osteophytosis, or osteomalacia (dependent on amount of fluoride ingested) with resultant abnormal bone formation, altered mechanical properties, increased remodeling, and increased resorption of bone
TYPICAL CLINICAL FINDINGS:
- Acute Intoxication:
- Gastroenteritis, convulsions, lethargy, collapse, death
- Chronic Intoxication:
- Mottling and abrasion of teeth
- Intermittent lameness
- Periosteal hyperostosis (demonstrated via radiography)
- Greater than 6 ppm fluorine in the urine
TYPICAL GROSS FINDINGS:
- Acute intoxication:
- Gastrointestinal ulceration and other nonspecific gross lesions
- Chronic intoxication:
- Pathognomonic lesions involve the teeth and bones
- Teeth: (Note: Dental lesions develop only when the flourosis is present and active when the tooth is being formed. Once the tooth is fully formed, it is not affected by flourosis.)
- Presence of small foci with a dry, chalky appearance compared to the normal glistening surface of the enamel
- Hypoplastic enamel evidenced by punctuate pits or horizontal grooves
- Excessive attrition
- In severe cases, all enamel in affected teeth may be chalky, opaque, and show varying degrees of yellow, dark brown, or black discoloration (virtually pathognomonic for fluorosis)
- Lesions are bilateral and usually affect incisors first, followed by premolars and molars
- Teeth exhibit enamel hypoplasia, irregular wear, malocclusion, and fractures
- Lesions may develop in the deciduous teeth of calves exposed during gestation
- Bone: (Note: Lesions are generalized but not uniform; in severe cases, lesions are characterized grossly by the formation of periosteal hyperostosis)
- Lesions occur first on the medial surface of the proximal third of the metatarsal and later on the mandible, metacarpals, and ribs
- Pelvis, vertebrae, and other bones of the distal pelvis are also affected
- Chalky-white and brittle bones with increased outer circumference
- In chronically infected animals, fracture of the medial claw is common, leading to lameness and a “cross-legged” stance
- Typically, no joint involvement
- Pathognomonic lesions involve the teeth and bones
TYPICAL LIGHT MICROSCOPIC FINDINGS:
- Acute intoxication:
- Gastrointestinal ulceration, nephrosis, and other nonspecific microscopic changes
- Chronic intoxication
- Ameloblasts are disorganized and small, with enamel malformation, and hypoplasia
- Odontoblasts are disorganized and vacuolated and have excessive production of predentin and globular dentin
- Outer layer of enamel is hypomineralized; incremental lines in the enamel are disrupted and the normal subsurface pigment band of bovine incisors is distorted
- Fibrosis of pulp cavity with ectopic bone formation
- Cementum hyperplasia
- Bone: (Note: Lesions are variable and are often influenced by age, species, fluoride compound, and toxic dose)
- Mottled osteons and lamellae with abnormal and tangled osteocytes
- Ground bone may display brown discoloration of osteons, similar to enamel
- Sections of cortex may have a mottled appearance with lamellae in some osteons showing discoloration with others appearing normal
- Osteosclerotic changes: Bony trabeculae are thick, dense, and have sharp heavy outlines, with reduced inter-trabecular marrow spaces
- Osteoporotic changes: Endosteal resorption enlarges the medullary cavity and may involve the laminar periosteal bone; this may result in hyperostosis
ADDITIONAL DIAGNOSTIC TESTS:
- Serum and urine fluoride levels
- Discolored teeth in cattle
- Congenital porphyria: Deficiency of uroporphyrinogen III cosynthetase results in production of uroporphyrinogen I and coproporphyrinogen I (photodynamic); teeth are pink; not discolored or mottled, pitted, or eroded
- Tetracycline administration: especially during mineralization; toxic to ameloblasts; deposited into dentin during mineralization; yellow teeth
- Osteogenesis imperfecta: Defect in dentin production with marked thinning of dentin and irregular dentinal tubule formation; teeth are pink due to the visibility of dental pulp through the thin crown
- Guinea pigs fed diets high in fluorine:
- Vitamin C and calcium deficiencies may aggravate condition
- Deformed and irregular molars and incisors cause profuse salivation (“Australian slobbers”); brittle bones and exostosis
- Ingestion of rodenticide sodium monofluoroacetate (Compound 1080)
- Overdose with fluorinated anesthetic gases (methoxyflurane or halothane)
- Pigs, chickens: Improper use of sodium fluoride anti-parasitic compounds used to treat internal parasites in swine and external parasites in chickens
- Young growing dogs and pigs (presumably other species): Lesions resemble rickets due to the inhibition of mineralization when fluoride is present in high doses; ends of long bones and the costochondral junctions are enlarged while the physes are increased in depth, softer than normal, and yield to the pressure of weight bearing
- Rabbits: Spontaneously occurring proliferative gastroduodenopathy and endosteal and periosteal hyperostosis
- Wild ungulates ( wild red deer): Among subadults, tephra (volcanic ash) caused pathologic development of newly emerging teeth typical of fluorosis, including enamel hypoplasia, breakages, pitting, mottling, and extremely rapid ablation of entire crowns down to underlying pulp cavities; the loss of teeth functionality affected physical condition, and none of the subadults were able to conceive
- Marsupials (Eastern Grey Kangaroos): Formation of multiple, large, smooth exostoses over the diaphysis of long bones and degenerative joint disease
- Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Blackwell Publishing; 2016: 315.
- Bock P, Peters M, Bago Z, Wolf P, Thiele, Baumgartner W. Spontaneously occurring alimentary osteofluorosis associated with proliferative gastroduodenopathy in rabbits. Vet Pathol. 2007;44:703-706.
- Craig LE, Dittmer KE, Thompson KG: Bones and joints. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 1, 6th ed. St. Louis: Elsevier; 2016:84-86.
- DeBay B, Jacob B, Oehme FW, Imerman P. Sodium fluoride/copper naphthenate toxicosis in cattle. J Vet Diagn Invest. 2007:19:305-308.
- Flueck WT, Smith-Flueck JA. Severe dental fluorosis in juvenile deer linked to a recent volcanic eruption in Patagonia. J Wildl Dis. 2013 Apr;49(2):355-66.
- Gelberg HB. Alimentary system and the Peritoneum, Omentum, Mesentery, and Peritoneal Cavity. In: Zachary JF, eds. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Inc; 2017:351.
- Hufschmid J, Beveridge I, Coulson G, et al. Skeletal pathology of eastern grey kangaroos (Macropus giganteus) exposed to high environmental fluoride levels in South-Eastern Australia. J Comp Pathol. 2015;153(2-3):167-84.
- Maas J. Fluorosis. In: Smith BP, ed. Large Animal Internal Medicine. 5th ed. St Louis, MO: Mosby; 2015:1122-1123.