The Cardiopulmonary Effects of Sodium Fluoroacetate (1080) in Sprague-Dawley Rats

Abstract

Sodium fluoroacetate (1080) is a highly toxic metabolic poison that has the potential because of its lack of defined color, odor, and taste and its high water solubility to be intentionally or unintentionally ingested through food adulteration. Although the mechanism of action for 1080 has been known since the 1950's, no known antidote exists. In an effort to better understand the cardiopulmonary impacts of 1080, we utilized whole-body plethysmography and telemeterized Sprague-Dawley rats which allowed for the real-time measurement of respiratory and cardiac parameters following exposure using a non-invasive assisted-drinking method. Overall, the animals showed marked depression of respiratory parameters over the course of 24 hours post-exposure and the development of hemorrhage in the lung tissue. Tidal volume was reduced by 30% in males and 60% in females at 24 hours post-exposure, and respiratory frequency was significantly depressed as well. In telemeterized female rats, we observed severe cardiac abnormalities, highlighted by a 50% reduction in heart rate, 75% reduction in systolic blood pressure, and a 3.5-fold lengthening of the QRS interval over the course of 24 hours. We also observed a reduction in core body temperature of nearly 15°C. Our study was able to describe the severe and pronounced effects of sodium fluoroacetate poisoning on cardiopulmonary function, the results of which indicate that both tissue specific and systemic deficits contribute to the toxicological progression of 1080 intoxication and will need to be accounted for when developing any potential countermeasure for 1080 poisoning.

Keywords: 1080; Pesticides; Real-Time Physiology; Sodium fluoroacetate; Toxicology; cardiopulmonary; metabolic poison.

Figure 1.. Lung Histology of Rats Exposed to 0.85 LD₅₀.

Both male and female rats were exposed to a 0.85 LD₅₀ dose of 1080. Rats were observed for 24 hours in a whole-body plethsymograph chamber and euthanized at 24 hours. Tissues were collected for histological analysis by H&E staining. Hemorrhage was observed in the lungs of 7 of the 8 exposed animals examined. There was no observed difference between the male and female tissues. A) Control left lung lobe 40x, B) Control left lung lobe 200x, C) Exposed left lung lobe 40x, D) Exposed left lung lobe 200x.

Figure 2.. Analysis of BALF in Exposed Male Rats.

Male rats were exposed to a dose of 0.85 LD₅₀ 1080. Rats were observed for 24 hours in a whole-body plethysmograph chamber and then euthanized. A bronchoalveolar lavage was performed on the left lung, and the fluid was collected for analysis. Protein content in the BALF was determined by a Pierce 660 nm assay. A) Significant increase in BALF protein was observed in the exposed animals. B) BALF absorbance at 540 nm, which corresponds with hemoglobin’s absorbance peak, was investigated. Although we did observe red-tinged BALF in some of the exposed animals, we did not see a significant increase in all of the exposed. Bars = mean, n = 6–9, *p < 0.05, Student’s t-test.

Figure 3.. Tidal Volume of Rats after Exposure to 1080.

Both female (A) and male (B) rats were exposed to a 0.85 LD₅₀ dose of 1080 and observed in a whole-body plethysmograph chamber for 24 hours. We observed an overall decrease in the tidal volume, starting about 30 minutes after exposure. The decrease plateaued, even after major convulsions (~1.5 hours). In females a second decrease occurred from 2 hours to 10 hours. In males we did not observe a further decrease in tidal volume after the initial decrease at 30 minutes. Blue = Smooth fit of Control, Red = Smooth fit of Exposed, Females – n = 4–8, Males n = 7–19

Figure 4.. Respiratory Frequency of Rats Exposed to 1080.

Both female (A) and male (B) rats were exposed to a 0.85 LD₅₀ dose of 1080 and observed in whole-body plethysmograph chambers for 24 hours. We observed, in both female and males, a sharp increase in frequency around 30 minutes. The increase was short lived, and a steady decrease was observed in each sex. In the females the decrease in respiratory frequency plateaued at 10 hours post-exposure, and in the males the plateau was at 6 hours. The increase in control frequency, observed in post-exposure hours 2–18, corresponds with the animals’ normal active periods. Blue = Smooth fit of Control, Red = Smooth fit of Exposed, Females – n = 4–8, Males n = 7–19.

Figure 5.. The Effects of 1080 on Cardiac Parameters in Female Rats.

Female rats were administered a 0.85 LD₅₀ dose of 1080, and cardiac parameters were monitored using an implanted telemetry device. We observed pronounced impacts on cardiac function over the course of 24 hours. A) Heart rate remained normal in the controls during the latency period, but fell sharply over the course of 10 hours following onset of whole-body convulsions. B) QRS interval mirrored the heart rate and only increased following the onset of whole-body convulsions. C) Systolic blood pressure started decreasing immediately after administration of 1080 and was reduced by 50% at the end of the study. Blue = Smooth fit of Control, Red = Smooth fit of Exposed, n = 4–8

Figure 6.. Cardiac Glutathione Levels Following Exposure to 1080 in Male Rats.

Twenty-four hours after exposure to a 0.85 LD₅₀ dose of 1080, male rats were euthanized, and heart tissue was collected. Total glutathione levels in the heart were assessed from homogenized tissue using a colorimetric assay. We observed a nearly 50% decrease in the total glutathione levels in animals that had been exposed to 1080. This may indicate both cardiac dysfunction and increased fluoroacetate defluorination in the heart tissue. Male rats, Bar = mean, n = 6–7, *p < 0.05 Student’s t-test.

Figure 7.. The Effect of 1080 Exposure on Core Body Temperature in Female.

Female rats were exposed to a 0.85 LD₅₀ dose of 1080, and core body temperature was measured using an implanted telemetry device. We observed a severe decrease in core temperature of approximately 15°C in the exposed animals. This indicates a significant inability to thermoregulate after 1080 exposure. Female rats, n = 4–8, Blue = Smooth fit of Control, Red = Smooth fit of Exposed.