Co-operative effects of thoracic X-ray irradiation and N-nitrosobis(2-hydroxypropyl) amine administration on lung tumorigenesis in neonatal, juvenile and adult Wistar rats

Assessment of risks associated with childhood exposure to ionizing radiation when combined with chemical carcinogens is of great importance. We studied the age-dependence of the effect of combined exposure to ionizing radiation (IR) and a chemical carcinogen on lung carcinogenesis. Female 1-, 5-, and 22-week-old Wistar rats were locally irradiated on the thorax with X-rays (3.18Gy) and/or were injected intraperitoneally with N-nitrosobis(2-hydroxypropyl)amine (BHP) (1g/kg body weight) 1week after X-ray exposure or at 23weeks of age. Rats were terminated at 90weeks of age. We found that: (i) the incidence of lung tumors (adenoma and adenocarcinoma) increased slightly as a function of age at X-ray exposure, although this was not statistically significant, while the incidence induced by BHP decreased with increasing age at administration; (ii) combined exposure to X-rays at 5 or 22weeks with BHP 1week later enhanced the tumor incidence, and the effect at early-life stage (5weeks irradiation) was more effective than that at late-life stage (22weeks irradiation); (iii) combined exposure preferentially enhanced malignant transformation; (iv) although a longer interval between the X-ray and BHP treatments reduced the combined effect, risks of early-life irradiation at 1 or 5weeks of age lasted into adulthood; (v) adenomas and adenocarcinomas induced by X-ray and/or BHP originated from surfactant apoprotein A-positive alveolar type II cells; and (vi), extracellular signal-regulated kinase pathway activation was observed in half the adenocarcinomas, regardless of the exposure schedule. In conclusion, combined exposure may enhance lung tumorigenesis more synergistically at early-life stage (5weeks of age) than later-life stage. ► Rat lung tumor rates after thoracic X-ray irradiation increased with age at exposure. ► Lung tumor incidence after BHP decreased with age at administration. ► X-ray irradiation at 5 or 22weeks with BHP 1week later enhanced tumor induction. ► Effects of irradiation at 1 or 5weeks persisted in adults and were enhanced by BHP. ► ERK was activated in half of adenocarcinomas, regardless of the exposure schedule.