Enhancement of myelotoxicity induced by repeated irradiation in mice exposed to a mixture of groundwater contaminants

Abstract

As part of a program on the toxicology of chemical mixtures at the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP), hematopoietic functions were studied in female B6C3F₁ mice treated with 0, 1%, and 5% of a chemical mixture stock of 25 groundwater contaminants in drinking water for 31.5 weeks. The toxicologic interaction between continuous exposure to groundwater contaminants and stress induced by multiple irradiation on hematopoiesis was investigated. For those mice receiving both the chemical mixture and irradiation, the exposure to the former was continuous throughout the 31.5-week experimental period, whereas whole body irradiations (4 times at 200 rads/each) were carried out at 7-week intervals with the first one at 3.5 weeks. Myelotoxicity assessment was made by determining the number of granulocyte-macrophage progenitor cells (CFU-GM) 1 week after each irradiation and also at 6 weeks following irradiation as a measure of recovery from stress. Non-irradiated mice treated with 5% chemical mixture solution showed suppression of CFU-GM after 15.5 weeks and became progressively more affected (only 70% of controls by 31.5 weeks of treatment). The population of CFU-GM in mice treated with 5% chemical mixture for 4.5 weeks plus irradiation (1 week after first irradiation) was only 22% of the non-irradiated vehicle control group. This combined (i.e., chemical mixture plus irradiation) suppression of CFU-GM intensified after repeated irradiation until the number of CFU-GM was only 10.7% following the fourth irradiation at 25.5 weeks. Thus, irradiation caused a significant reduction in CFU-GMs in all mice but the effects were more pronounced in mice treated with a chemical mixture. In the chemical mixture pretreated mice, the hematopoietic cells were depressed more by multiple irradiation, and the recovery was delayed as compared to non-irradiated control. Furthermore, even at 1% mixture stock level (the lowest concentration tested), when all routine hematologic or conventional toxicologic endpoints appeared to be normal, an enhancement of radiation injury to hematopoiesis was detected. It is suggested that a residual, subclinical, bone marrow effect of the chemical mixture renders the mice more sensitive to subsequent irradiation-induced injury and also prolongs the recovery of mice following multiple irradiation. These findings suggest that long-term exposure to highly contaminated driking water may render a population more susceptible to subsequent hematopoietic stress.