Toxicology and carcinogenesis studies of transplacental AZT (Cas No. 30516-87-1) in Swiss (CD-1®) mice (in utero studies).

UNLABELLED

3'-Azido-3'-deoxythymidine (AZT) is the most widely used and evaluated chemotherapeutic agent for the treatment of persons with acquired immune deficiency syndrome (AIDS) and persons seropositive for human immunodeficiency virus (HIV). The study in this report was conducted to obtain information on AZT transplacental carcinogenicity at doses that were lower than those used in previous NCI studies and analogous to therapeutic doses. Male and female Swiss (CD-1(R)) mice were exposed to AZT (greater than 99% pure) during all of gestation. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. Groups of 22, 28, 34, or 46 female mice (F(0) generation) were administered AZT in 0.5% methylcellulose by gavage at doses of 50, 100, 200, or 300 mg AZT/kg body weight 7 days per week for 29 to 39 days (day of delivery). A vehicle control group of 22 female mice received methylcellulose alone. Each female group was divided into two groups with dosing started 1 week apart in order to facilitate cohabitation, mating, and delivery. Groups of six, six, seven, nine, or twelve undosed male mice were cohabited with the vehicle control and 50, 100, 200, and 300 mg/kg dosed females, respectively, on study days 9 to 13 and then discarded. Pups (F(1) generation) were culled (0, 50, and 100 mg/kg groups) to yield a maximum of five pups/sex per litter on postnatal day 4; no more than four pups/sex per litter were used in the study. On postnatal day 25, all surviving 200 and 300 mg/kg pups were placed on study. After culling and randomization to cage groups, the 0, 50, 100, 200, and 300 mg/kg groups consisted of 50, 50, 50, 37, and 32 male pups and 50, 50, 50, 40, and 42 female pups, respectively. Decreased litter size and fertility rates were observed in the 200 and 300 mg/kg F0 dams. Survival of all exposed groups of F(1) mice was similar to that of the vehicle controls. Mean body weights of 200 mg/kg males were generally less than those of the vehicle controls after week 29. Mean body weights of 300 mg/kg males were less during the first year of the study, but these mice recovered and body weights were generally similar to those of the vehicle controls at the end of the study. The incidences of alveolar/bronchiolar carcinoma and of adenoma or carcinoma (combined) in 200 and 300 mg/kg males were significantly greater than those in the vehicle controls. The incidences of histiocytic cellular infiltration of the lung in 200 and 300 mg/kg males were significantly increased.

GENETIC TOXICOLOGY

The NTP conducted a number of studies of the genetic toxicity of AZT, independent of this transplacental carcinogenicity study. In these genetic toxicity studies, AZT (50, 75, 100, or 150 mg/kg) administered to pregnant Swiss (CD-1(R)) dams, beginning prior to conception and continuing throughout gestation and lactation, induced high levels of micronucleated polychromatic erythrocytes (PCEs) in pups sampled on postnatal days 1 and 4. Direct gavage treatment of these transplacentally and lactationally exposed pups, beginning on postnatal day 4, resulted in further increases in the frequencies of micronucleated PCEs on postnatal days 8 and 21. The percentage of PCEs among erythrocytes in pups was significantly elevated over normal adult levels, indicating a high rate of erythropoiesis in neonatal mice. The percentage of PCEs was decreased in all pups exposed to AZT, consistent with treatment-related bone marrow toxicity.

CONCLUSIONS

Under the conditions of this study, there was clear evidence of carcinogenic activity in F(1) male mice exposed transplacentally to AZT based on increased incidences of alveolar/bronchiolar neoplasms. There was no evidence of carcinogenic activity in F(1) female mice exposed transplacentally to AZT at 50, 100, 200, or 300 mg/kg. Reproductive toxicity in the form of decreased litter size and fertility rates was observed in dams in the 200 and 300 mg AZT/kg dose groups.