Determination of the historical changes in primary and secondary risk factors for cancer using U.S. public health records

Abstract

Overall cancer mortality rates have risen from about 4% of all deaths in the early 20th century to about 25% of all deaths by the end of the century in the United States. To assess any potential hypotheses for this increase required knowledge of the mortality rate changes specific to each form of cancer, and the time points when these rates had changed. For this purpose, population and cancer mortality data of the U.S. were collected and organized to create age-specific mortality rates for each birth decade from the 1800s forward, delineated by the organ of incidence. Concurrently, cancer survival data were collected so as to correct for any effect of improved treatment on historical changes in cancer mortality rates. To analyze these data, a mathematical model for the three-stage process of carcinogenesis (initiation, promotion, and progression) was developed to estimate for each birth decade cohort the value of the fraction of the cohort at lifetime risk for that cancer, the value of the growth rate of the respective precancerous lesion, and the values for the mutation rates of normal and precancerous cells in the organ of incidence. This methodology permits the analysis of the potential historical effect of new chemical exposures during the last century on cancer mortality rates. These chemical exposures represent potential risk factors that determine the fraction of the population at risk of developing cancer (lifetime, primary risk factor), or that hasten death by cancer by altering either mutation or cell kinetic rates (accelerating, secondary risk factor.)

(cont.) COLON CANCER: Application of this model on the colon cancer mortality data resulted in the estimate that 42% of the population in the U.S. was at risk for developing colon cancer, independent of gender or race. More importantly, there was no significant historical change in the calculated fraction at risk for birthyear cohorts from 1860 to 1940, suggesting that the primary risk factors for colon cancer are not environmental. Although direct observation of in vivo mutation rates of colonic cells does not yet exist, the calculated rate for the first initiation mutation in the colon was interestingly found to be similar to the mutation rate observed for the hprt locus in human peripheral T-cells (-2.1 x 10-7 per cell year) and the spontaneous mutation rate of the hprt locus of human B-cells in culture. The estimate for initiation mutation rates increased no more than two-fold from the birthyear cohort of 1860 to the birthyear cohort of 1940, except for European American females for which calculated initiation mutation rates were historically invariant, but since the accuracy of primary data for mortality rates and survival rates cannot be ascertained, the apparent small differences might admittedly arise from unknown biases. Evaluation of the parameter of the growth rate of precancerous lesions showed no significant historical change on this parameter. Curiously, the calculated doubling rate of these lesions (-0.17-0.21) was found to be similar to the growth rate of children, suggesting that the required initiation events have the net effect of potentially reactivating pathways involved in child development.

(cont.) The predominant historical change in the observed mortality rates for colon cancer occurred only at old ages. ...