Carcinogen—DNA adducts and gene mutation in foundry workers with low-level exposure to polycyclic aromatic hydrocarbons

Abstract

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.

A Critical Evaluation of DNA Adducts as Biological Markers for Human Exposure to Polycyclic Aromatic Compounds

“…There is sufficient circumstantial evidence to assume that DNA adducts are actually related to cancer risk in man. For example, Perera et al (1994) reported a correlation between DNA adduct levels and the in vivo mutation frequency in individuals occupationally exposed to PAH. Although the gene (HPRT) and tissue (white blood cells, WBC) under investigation, are not relevant in occupationally related carcinogenesis, their results provide evidence for the mutational effects of PAH in vivo in humans.…”

Cytogenetic analysis of foundry molders using the micronucleus frequency in exfoliated buccal mucosa

“…Similarly, reference number [21] reported a link between carcinogen DNA adducts and somatic gene mutation at the hypoxanthine guanine phosphoribosyl transferase locus in an iron foundry workers exposure to benzo[a]pyrene and other polycyclic aromatic hydrocarbons (PAHs).…”

Molecular Epidemiology in Environmental Carcinogenesis

“…Several recent studies have examined whether baseline levels of micronutrients (vitamins C, E, ,-carotene, or retinol) in the serum of persons who have not been treated with chemoprevention are inversely related to genetic damage (9,13). In a cross-sectional study of 63 heavy smokers, the serum concentrations of a-tocopherol (cholesterol-adjusted), ascorbic acid, 1-carotene, and retinol were evaluated in relationship to the levels of PAH-DNA adducts in lymphocytes measured in the same individuals (14).…”