Recent molecular epidemiologic research provides compelling new evidence that environmental factors are major contributors to human cancer and that their risks are strongly influenced by genetic and acquired susceptibility. In particular, molecular epidemiology has demonstrated substantial variability in biologic response to carcinogens and suggests that certain groups-such as the very young, those with predisposing genetic traits or nutritional deficits, and even certain ethnic groups-are likely to have greater risk from selected exposures than other members of the population. This work implies that major gains in prevention of cancer, which will claim more than 554 000 American lives this year, will necessitate health and regulatory policies that protect these more susceptible groups and individuals from risks of man-made and naturally occurring environmental carcinogens. The specific implication from this research is that, to be effective in prevention, risk assessments developed in support of these policies by regulatory bodies, such as the Environmental Protection Agency, should reflect the available scientific data on individual variability in both exposure and susceptibility.

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Molecular Epidemiology: Insights Into Cancer Susceptibility, Risk Assessment, and Prevention

Publisher Summary Chemical carcinogenesis research has substantially broadened the understanding of the cellular and molecular changes involved in cancer development and provided new information on cell biology. The association of chemicals as causative factors in human cancers, the development of in vivo and in vitro experimental models, and technical advances facilitating a molecular approach to problems in cell biology have provided the impetus for progress in this research area. This chapter presents the newer experimental models and techniques that have built on the early observations to enhance the understanding of the process of cancer development at the molecular level. The chapter focuses on conceptual advances in chemical carcinogenesis research and describes to a limited extent the experimental data upon which they are founded. Carcinogenesis is evaluated as a multistage process in which the summation of events is required to produce a cancer. The first stage, initiation, is defined as the consequences of the initial interaction of a tissue with carcinogen. Promotion, the second stage, is confined to those processes which facilitate the expression of the initiated phenotype at the tissue level. Promotion may result from the influence of promoting agents on the entire tissue or on the initiated cells.

Chemical carcinogenesis: from animal models to molecular models in one decade.

The presence of covalent DNA chemical addition products (adducts) in human term placentas was investigated by recently developed immunologic and 32P-postlabeling assays. DNA from placental specimens of smokers showed a small but not statistically significant increase in adduct levels when tested by antibodies to DNA modified with a benzo[a]pyrene dihydrodiol epoxide (BPDE-I), the ultimate carcinogenic derivative of benzo[a]pyrene. The postlabeling assay detected several modified nucleotides, one of which (adduct 1) strongly related to maternal smoking during pregnancy. This adduct was present in placental tissue from 16 of 17 smokers, but only 3 of 14 nonsmokers. Among smokers, levels of adduct 1 in general were only weakly related to questionnaire and biochemical measures of the intensity of smoking exposures, which suggests modulation by individual susceptibility factors. The adduct seemed to be derived from an aromatic carcinogen, but it may not result from several of the most intensely studied polycyclic aromatic hydrocarbons or aromatic amines in tobacco smoke. The data show the association of cigarette smoking with covalent damage to human DNA in vivo.

https://science.sciencemag.org/content/sci/231/4733/54.full.pdf

Detection of smoking-related covalent DNA adducts in human placenta

Biomonitoring of polycyclic aromatic hydrocarbons in human urine.

Biomonitoring of polycyclic aromatic hydrocarbons in human urine

Metabolic activation of benzo(a)pyrene (BP) to its ultimate carcinogenic form, 7β,8α-diol-9α,10α-benzo(a)pyrene epoxide (BPDE), and the binding of BPDE to DNA are important steps in BP carcinogenicity in experimental animals. Since people of certain occupations are exposed to high concentrations of BP, we have used enzyme-linked immunosorbent assay and ultrasensitive enzymatic radioimmunoassay to measure BPDE:DNA adducts in white blood cells from 2 of these occupational groups. Seven of 28 samples from roofers and 7 of 20 samples from foundry workers were positive for BPDE:DNA adducts (range, 2 to 120 fmol BPDE/50 μg DNA). In a group of nine volunteers without these industrial exposures to BP, the two positive DNA samples were from cigarette smokers. Control DNA obtained from human lymphocyte cell line RPMI 4265 was negative. These results indicate that the metabolic activation of BP and formation of BPDE:DNA adducts occurs in humans.

https://cancerres.aacrjournals.org/content/canres/45/1/66.full.pdf

K. Hemminki

Papers

Detection of benzo(a)pyrene:DNA adducts in human white blood cells.