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Carcinogen-DNA adducts and somatic gene mutation at the hypoxanthine guanine phosphoribosyl transferase (HPRT) locus were evaluated in peripheral leukocytes of workers in an iron foundry with exposure to benzo[a]pyrene (B[a]P) and other polycyclic aromatic hydrocarbons (PAHs). During the two year study period, B[a]P exposure declined by approximately 40%, from a maximum of 60 ng/m3 in the first year to < 36 ng/m3 1 year later. A total of 64 persons were sampled in November/December of the two successive study years; 24 of them gave two samples one year apart. The biomarkers included carcinogen-DNA adducts in leukocytes (PAH-DNA measured by an immunoassay, aromatic-DNA by the 32P-postlabeling method) and HPRT mutation in lymphocytes. After adjusting for smoking, levels of PAH-DNA, aromatic-DNA and HPRT mutation frequency (Mf) increased with exposure among the 64 workers sampled during the 2 year period (P < or = 0.05). However, the markers showed a differential response to the change in exposure, consistent with their individual biology. For example, among the 24 workers sampled in both years, carcinogen-DNA adducts (which have a half-life on the order of several months) were markedly reduced from the first to the second year (PAH-DNA, 6.2 versus 2.3/10(8); aromatic-DNA, 2.5 versus 1.4/(8); P < 0.01). HPRT Mf (a longer-lived marker) was somewhat less affected by the decline in exposure (1.3 versus 0.8, P < or = 0.05). Moreover, in the second year several long-term workers had low levels of adducts, but elevated HPRT Mf. Thus, PAH-DNA and HPRT Mf were highly correlated in the first year (n = 17; r = 0.67; P < 0.01), but not in the second year or in the two years combined. However, when analysis was restricted to workers with detectable levels of adducts (who included the more highly exposed workers) the correlation was significant between PAH-DNA and HPRT (n = 17; r = 0.65; P = 0.005). In contrast, aromatic-DNA adducts and HPRT were not correlated in either year. These results suggest a molecular link between somatic gene mutation and PAHs; and they highlight the need in such molecular epidemiologic studies to consider the varying lifetimes of the individual markers.

Effective prevention of cancer requires sensitive early warning systems to identify groups, and ultimately individuals, who are at high risk of developing cancer and to accurately estimate the magnitude of their risk. Incorporated with molecular epidemiologic studies, biologic markers have the potential to provide quantitative human data on the biologically effective dose of carcinogens, resultant molecular effects, and genetic/acquired factors that modulate these effects. Clearly, this information is directly relevant to risk identification and to risk quantification.

A new technique for detecting oncogene activation based on immunoblotting for oncogene proteins in serum has been applied to screen a cohort of foundry workers with well-defined workplace exposures to polycyclic aromatic hydrocarbon carcinogens. Three of the 18 individuals screened were found to have abnormal expression of the proteins of the ras and fes oncogenes. These three individuals were known to have had medium to high workplace exposures to benzo(a)pyrene and to have correspondingly high levels of benzo(a)pyrene-DNA adducts in their peripheral leukocytes. No individuals among the unexposed controls were found to have abnormal serum oncogene protein expression. These results suggest the feasibility of using serum oncogene proteins along with DNA-carcinogen adducts as potential molecular epidemiological markers in exposed worker populations; further, larger scale studies will be necessary to demonstrate the utility of these markers for identifying individuals at risk for the development of malignant disease due to their occupational exposures.