90-Day Toxicity Study of Dichloroacetate in Dogs
J. L. CICMANEC*, L. W. CONDIE*, G. R. OLSON and SHIN-RU WANG
*Toxicolgy and Microbiology Division, Health Effects Research Laboratory Cincinnati, Ohio 45268 Pathology Associates, Inc. 6217 Centre Park Drive, Westchester, Ohio 45069 Computer Sciences Corporation Cincinnati, Ohio 45268
Received September 25, 1990; accepted April 18, 1991
90-Day Toxicity Study of Dichloroacetate in Dogs. CICMANEC, J. L., CONDIE, L W., OLSON, G. R., AND WANG, S. R. (1991). Fundam. Appl. Toxrcol. 17,376–389.
Male and female juvenile beagle dogs were dosed daily for 90 days with dichloroacetate (DCA). The compound was administered orally was gelatin capsules at doses of 0, 12.5, 39.5, and 72 mg/kg/day. Each dose group consisted of five males and five females. The dogs were observed clinically and blood samples were taken at 15-day intervals for hematologic and serum chemistry values. Decreased total erythrocyte count and hemoglobin levels were observed in mid- and high-dose beginning at Day 30. Serum concentrations of LDH were elevated at Days 30 and 45 in females and at Day 75 in males treated with DCA at 72 mg/kg/day. One female of the high-dose group died at Day 50 and two high-dose males died at Days 51 and 74. Hindlimb partial paralysis was observed in many high-dose dogs Vacuolization of myelinated white tracts of cerebrum, cerebellum, and/or spinal cord was observed in many high-dose dogs as well as some mid- and low-dose subjects Degeneration of testicular germinal epithelium and syncytial giant cell formation was noted in males of all dose groups. Hepatic vacuolar change and chronic hepatitis appeared only in DCA-treated dogs. In addition, suppurative bronchopneumonia and chronic pancreatitis were noted in many high-dose and some middose subjects. A "no-adverse-effect level" was not determined In this study.
Typical Side Effects of DCA in Animals
The following is extracted from "90-Day Toxicity Study of Dichloroacetate in Dogs"
Low dose was 12.5 mg/kg/day. Medium dose was 39.5 mg/kg/day. High dose was 75 mg/kg/day
Adverse effects noted in the low-dose group (12.5 mg/kg-day) included:
1. testicular degeneration
2. mild to moderate hepatic vacuolization in males and females
3. mild vacuolization of the myelinated white tracts of the cerebrum and cerebellum in males
Overt clinical signs were evident in the high-dose animals throughout the duration of the experiment:
1. Dyspnea (shortness of breath or difficulty in breathing) was observed in high-dose animals starting at day 45, and worsened with time.
2. Partial paralysis of the hind limbs was observed in three animals in the high-dose group during the latter half of the exposure period.
3. Conjunctivitis (pinkeye) was observed in 24/30 treated animals and a few controls during the first month, and became more severe later in the study.
4. The occurrence of ocular effects appeared to be dose-related, with 8 of 10 high-dose dogs affected.
5. Reduced food and water intake was noted in DCA-treated dogs, although the effect did not appear to be dose-related.
6. High-dose males exhibited a 16% reduction in body weight, while high-dose females and mid-dose males experienced a 9% reduction in weight gain over the duration of the study. Mid-dose females exhibited an 11% reduction in weight gain.
7. Dogs in the mid- and high-dose groups experienced sporadic diarrhea.
8. The most severely affected dogs required fluid therapy to prevent severe dehydration.
9. One female and two males treated at 72 mg/kg-day died during the study. The deaths were attributed to pneumonia and dehydration.