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

Childhood exposure to ionizing radiation (IR) and daily secondhand smoke increases the risk of developing lung cancer. Assessment of risks associated with childhood exposure to IR when combined with chemical carcinogens is of great importance. We studied the age dependence of the effect of combined exposure to 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 sacrificed at 90 weeks of age. We found that: (i) the incidence of lung tumors (both adenomas and adenocarcinomas) increased as a function of the age at X-ray exposure, whereas it decreased with age after BHP administration; (ii) combined exposure to X-rays at 5 or 22 weeks with BHP 1 week later promoted adenomas and adenocarcinomas; (iii) although a longer interval between the X-ray and BHP treatments reduced the combined effect, carcinogenic events of early-life irradiation at 1 or 5 weeks of age lasted into adulthood; (iv) most tumors originated from surfactant apoprotein A-positive alveolar type II cells; and (v), extracellular signal-regulated kinase pathway activation was observed in half the adenocarcinomas, regardless of the exposure schedule. Lung carcinogenesis following IR and BHP exposure is dependent on age-atexposure. Combined exposure to X-rays and BHP promoted lung tumorigenesis, especially malignant tumors, for all ages of irradiation.