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Industrialized regions in Poland are characterized by high ambient pollution, including polycyclic aromatic hydrocarbons (PAHs) from coal burning for industry and home heating. In experimental bioassays, certain PAHs are transplacental carcinogens and developmental toxicants. Biologic markers can facilitate evaluation of effects of environmental PAHs on the developing infant. We measured the amount of PAHs bound to DNA (PAH-DNA adducts) in maternal and umbilical white blood cells. The cohort consisted of 70 mothers and newborns from Krakow, Poland, an industrialized city with elevated air pollution. Modulation of adduct levels by genotypes previously linked to risk of lung cancer, specifically glutathione S-transferase MI (GSTM1) and cytochrome P4501A1 (CYP1A1) Msp restriction fragment length polymorphism (RFLP), was also investigated. There was a dose-related increase in maternal and newborn adduct levels with ambient pollution at the women's place of residence among subjects who were not employed away from home (p < or = 0.05). Maternal smoking (active and passive) significantly increased maternal (p < or = 0.01) but not newborn adduct levels. Neither CYP1A1 Msp nor GSTM1 polymorphisms was associated with maternal adducts. However, adducts were significantly higher in newborns heterozygous or homozygous for the CYP1A1 Msp RFLP compared to newborns without the RFLP (p = 0.04). Results indicate that PAH-induced DNA damage in mothers and newborns is increased by ambient air pollution. In the fetus, this damage appears to be enhanced by the CYP1A1 Mspl polymorphism. Images Figure 1

Polymorphic metabolic genes that confer enhanced genetic susceptibility to the carcinogenic effects of certain environmental carcinogens act according to a type 2 interaction between genetic and environmental risk factors. This type of interaction, for which the gene has no effect on disease outcome by itself but only modifies the risk associated with exposure, must be treated differently from other types of gene-environment interaction. We present a method to analyze different dose effects often seen in studies involving these genes. We define a low exposure-gene effect, when a greater degree of gene environment interaction appears at lower doses of exposure (the interaction follows an inverse dose function), and a converse high exposure-gene effect, when the interaction increases as a function of dose. Using a standard logistic regression model, we define a new term, alpha, that can be determined asa function of exposure dose in order to analyze epidemiological studies for the type of exposure-gene effect. These models are illustrated by the use of hypothetical case-control data as well as examples from the literature. Images Figure 1

We present a model of biomarker validation developed in our laboratory, the results of the validation study, and the impact of the estimation of the variance components on the design of future molecular epidemiologic studies. Four different biomarkers of exposure are illustrated: DNA-protein cross-link (DNA-PC), DNA-amino acid cross link (DNA-AA), metallothionein gene expression (MT), and autoantibodies to oxidized DNA bases (DNAox). The general scheme for the validation experiments involves n subjects measured on k occasions, with j replicate samples analyzed on each occasion. Multiple subjects, occasions, and replicates provide information on intersubject, intrasubject, and analytical measurement variability, respectively. The analysis of variance showed a significant effect of batch variability for DNA-PC and MT gene expression, whereas DNAox showed a significant between-subject variability. Among the amino acids tested, cysteine and methionine showed a significant contribution of both batch and between-subject variability, threonine showed between-subject variability only, and tyrosine showed between-batch and between-subject variability. The total variance estimated through the experiment was used to calculate the minimum sample size required for a future epidemiologic study including the same biomarkers used for the reliability study. Such validation studies can detect the various components of variability of a biomarker and indicate needed improvements of the assay, along with possible use in field studies.

Current research indicates a role for several oncogenes in radiation-induced carcinogenesis in vivo and cell transformation in vitro. Certain oncogenes are probably also involved in some cases of human cancer caused by exposure to nonionizing radiation and may play a mechanistic role in the phenomenon of radioresistance seen in later stages of tumor progression. The mechanisms of oncogene activation seen in radiation-induced tumors include point mutations, gene amplification, and changes in gene expression. Genetic factors associated with target species, strain, and tissue type play an important role in determining the specific nature of oncogene activation by radiation exposure. Using the rat skin as a model for cancer induction by ionizing radiation, we found concurrent activation of K-ras and c-myc oncogenes in end-stage tumors. Amplification of the myc gene proved to occur during a late stage of tumor progression and is not an early initiating event resulting from the direct action of radiation on target cells. The importance of tissue specificity, tumor cell heterogeneity, and physical characteristics of the radiation exposure are discussed.

The field of environmental health science is now a recognized and respected branch of science in American and worldwide academia. One of the pioneers who had a major role in the establishment of environmental health as a true scientific discipline was Norton Nelson, the founder and first chair of the Department and the Institute of Environmental Medicine at New York University (NYU), which now bears his name. Among his many accomplishments, he played a leading role in the formulation of legislation that created the National Institute of Environmental Health Sciences (NIEHS) (Lippmann 2001). We would like to remind readers of some of the basic principles that Nelson and other pioneers of the new discipline invoked in order to establish environmental health science as an important discipline and to overcome barriers to acceptance of the field as a true science by those in other disciplines.

Epithelial cell cancers are induced in rat skin by ionizing radiation in a manner that is consistent with the dual action (i.e., two alterations) hypothesis of radiation effects on DNA. This hypothesis states simply that two initial alterations, presumably in the DNA, are necessary to start a normal cell on the pathway to cancer. The initial radiation-induced alteration in the DNA is repairable as indicated by the reduction in tumor incidence with increasing time between dose fractions; the repair halftime is estimated to be 3.0 +/- 1.0 hr. Theoretical predictions of a specific dependence of tumor incidence on linear energy transfer (LET) have been verified experimentally for two specific LET values. However, the theoretical formulation provides no guidance regarding the observed reduction in the carcinogenic action of radiation with age at the time of exposure. Analysis of the tumor DNA for oncogene activation indicated k-ras and c-myc oncogenes were activated in highly anaplastic rat skin cancers, whereas only one of these oncogenes, usually c-myc, was activated in comparatively benign basal cell carcinomas and in squamous cell carcinomas.

Techniques of molecular biology have been used to determine the relationship of cellular oncogenes to mechanisms of experimental carcinogenesis. Model systems involving three direct-acting alkylating carcinogens, two organ sites, and two species have been employed to elucidate the relationships between carcinogenic etiology, tissue specificity, and activation of known and novel oncogenes. Dimethylcarbamyl chloride, a reactive acylating agent, induces tumors of both the rat nasal mucosa and mouse skin whose DNA is devoid of NIH 3T3 transforming activity. Beta-propiolactone-induced rat nasal carcinomas contain a novel oncogene, 6 to 9 kb in size, whereas a mouse skin carcinoma induced by this agent possesses an H-ras oncogene activated by a 61st codon A to T transversion mutation. The novel oncogene activated in rat nasal tumors induced by beta-propiolactone is distinct from one found in methylmethane sulfonate-induced tumors. The implications of these findings for understanding how oncogenes fit into general mechanism of carcinogenesis are discussed.

Techniques of molecular biology have been used to determine the relationship of cellular oncogenes to mechanisms of experimental carcinogenesis. Model systems involving three direct-acting alkylating carcino? gens, two organ sites, and two species have been employed to elucidate the relationships between carcinogenic etiology, tissue specificity, and activation of known and novel oncogenes. Dimethylcarbamyl chloride, a reactive acylating agent, induces tumors of both the rat nasal mucosa and mouse skin whose DNA is devoid of NIH 3T3 transforming activity. /J-propiolaetone-induced rat nasal carcinomas contain a novel oncogene, 6 to 9 kb in size, whereas a mouse skin carcinoma induced by this agent possesses an H-ras oncogene acti? vated by a 61st codon A to T transversion mutation. The novel oncogene activated in rat nasal tumors in? duced by p-propiolactone is distinct from one found in methylmethane sulfonate-induced tumors. The implications of these findings for understanding how oncogenes fit into general mechanism of carcinogenesis are discussed.