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 (3.18 Gy) and/or were injected intraperitoneally with N-nitrosobis(2-hydroxypropyl)amine (BHP) (1 g/kg body weight) 1 week after X-ray exposure or at 23 weeks of age. Rats were terminated at 90 weeks 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 22 weeks with BHP 1 week later enhanced the tumor incidence, and the effect at early-life stage (5 weeks irradiation) was more effective than that at late-life stage (22 weeks 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 5 weeks 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 (5 weeks of age) than later-life stage.Highlights
▸ 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 22 weeks with BHP 1 week later enhanced tumor induction. ▸ Effects of irradiation at 1 or 5 weeks persisted in adults and were enhanced by BHP. ▸ ERK was activated in half of adenocarcinomas, regardless of the exposure schedule.