Chronic Systemic Toxicity Study of Copper Intrauterine Devices in Female Wistar Rats

Abstract

BACKGROUND The aim of this study was to evaluate the chronic systemic and local toxicity of a copper intrauterine device in a rat model. MATERIAL AND METHODS Cu-IUD fragments were inserted into the uterine horns of female Wistar rats for 26 weeks (equivalent 15.42-17.33 years in humans). We tested copper at 20, 40, and 60 times the clinical dosages to study copper toxicity under severe conditions. Classic chronic systemic toxicity evaluations, including body weight, hematology, organ coefficient, and tissue reactions, were performed. RESULTS The body weight of the rats increased during the 26 weeks, which showed that the Cu-IUD implant had no effect on animal growth. Histological examinations and organ coefficients of the uterus and other major organs indicated no obvious systemic or local impairment. Blood tests confirmed that the hepatic and renal functions remained normal. CONCLUSIONS These results obtained at different dosages and long-term implantation provide solid data confirming the safety of long-term use of Cu-IUDs. However, the elevated leucocyte levels found in this study warrant further investigation.

Figure 1

Insertion of the TCu220C copper sleeves. (A) After an incision was made, the IUD fragment was introduced into 1 uterine horn by means of an injector. (B) Then, a thread was loosely tied over the uterine horn, distally to the IUD, to prevent it from moving while keeping the horn open.

Figure 2

Change in body weight from baseline to 26 weeks post-intervention. The body weight of the rats in each group increased normally.

Figure 3

Change in body weight during the first 4 weeks post-intervention. Weight loss was observed shortly after the procedure in the surgical groups, but it gradually increased thereafter. After 2 to 3 weeks, the rats had regained their weight completely.

Figure 4

Histopathology of some major organs in group 6 (high-dosage group) 26 weeks after insertion of the TCu220C copper sleeves. (A) liver; (B) lung; (C) intestine; (D) kidney; (E) bone; (F) oviduct. No structural anomalies were observed (×100, hematoxylin-eosin stain).

Figure 5

Histopathology of the endometrium in groups 1 (blank group) and 6 (high-dosage group) at 26 weeks. (A, B): Blank (A: ×50; B: ×400); (C, D): 3 TCu220C copper sleeves in situ for 26 weeks (C: ×50; D: ×400). The presence of these 3 fragments of TCu220C for 26 weeks elicited a macrophage- and lymphocyte-based chronic inflammatory reaction and squamous metaplasia of the endometrial cells. Neither necrosis nor atypia was observed in the endometrium.