Faculty Bibliography

Propylene oxide (PO) is a widely used industrial reagent which is mutagenic and carcinogenic. We have recently shown that a variety of aliphatic epoxides, including propylene oxide, can react with DNA to form hydroxyalkyl adducts at N-3 of cytosine which rapidly undergo hydrolytic deamination to produce uracil adducts. These 3-hydroxyalkyl uracil adducts are stable in DNA and are postulated to be an important class of potentially mutagenic lesions. Mutagenesis at cytosine residues due to PO modification of single-stranded M13mp2/C141 DNA was studied by transfection of modified DNA into SOS and non-SOS induced E. coli host cells. Mutations of the proline (CCC) codon at C141 which result in reversion of the lacZ phenotype (blue plaques) were scored. It was found that PO treatment of single-stranded DNA results in dose-dependent mutagenesis that is highly SOS dependent. The spectrum of base-substitution mutations found at this site differed when PO-modified DNA was transfected into E. coli with different DNA repair backgrounds. These results indicate that propylene oxide induced DNA adducts at template cytosine residues are mutagenic in E. coli and that this mutagenesis is greatly increased by SOS processing. They also show that these lesions may be repaired by one or more mechanisms

Medical conditions related to hormonal abnormalities were investigated in a case-control study of breast cancer among women who attended a screening centre. Information was obtained by telephone interview regarding physician-diagnosed medical conditions such as thyroid or liver diseases, diabetes, and hypertension, as well as hirsutism, acne, galactorrhoea, and reproductive, menstrual, and gynaecological factors. Results are presented for 354 cases and 747 controls. Women with fertility problems who never succeeded in becoming pregnant were at significantly increased breast cancer risk (adjusted odds ratio [OR] = 3.5; 95% confidence interval [CI]:1.1-10.9). An elevated cancer risk was also associated with having excess body hair (OR = 1.5; 95% CI:1.0-2.3), or having excess body hair in addition to persistent adult acne (OR = 6.8; 95% CI:1.7-27.1). Recurrent amenorrhea (OR = 3.5; 95% CI:1.1-11.5), and a treated hyperthyroid condition (OR = 2.2; 95% CI:1.1-4.4) were significantly associated with risk. A non-significant elevation of risk was present for endometrial hyperplasia (OR = 1.8; 95% CI: 0.8-4.0). There was a suggestion of an association between a history of galactorrhoea and breast cancer risk (OR = 2.0; 95% CI:0.8-4.9) among premenopausal women. No associations were found with other medical or gynaecological factors. The possibility that some of these findings are due to chance cannot be excluded because of the problem of multiple comparisons

Prolactin, a hormone indispensable for milk secretion, has been shown to enhance the development and growth of mammary tumors in rodents; however, its importance in human breast cancer is uncertain. Serum prolactin levels are known to fluctuate considerably under normal conditions, and lack of precision in the hormone measurements may have contributed to the largely negative findings in humans to date. The purpose of this study was to investigate the reliability of prolactin measurements in women using stored serum from an ongoing prospective study of breast cancer. Separate groups of postmenopausal and premenopausal women who donated multiple blood samples at approximately 1-year intervals were studied. The reliability of a single log prolactin determination, as measured by the intraclass correlation coefficient, was 0.76 for the postmenopausal women (95% confidence interval, 0.66-0.85) and 0.48 for the premenopausal women (95% confidence interval, 0.31-0.62). These findings suggest that a single measurement is sufficient to characterize the serum prolactin level of postmenopausal women for epidemiological research. For premenopausal women, however, multiple samples are desirable. Controlling for phase of the menstrual cycle does not appear to substantially improve the reliability of premenopausal measurements

The carcinogenicity of electron radiation relative to argon ions in rat skin was examined, specifically investigating whether the linear-quadratic model is useful for predicting cancer yield for one type of radiation based on yields observed for a different type. Three experiments were conducted to obtain information on the relationship between cancer yield and the dose of electron radiation: (1) a conventional dose-response protocol where the number of rats per group was based on the expected tumor yield; (2) a multiple-fraction protocol designed to take advantage of yield additivity as a way to estimate carcinogenicity at lower doses; and (3) a protocol to examine the effect of age at the time of irradiation on the dose-response relationship for cancer induction. Published data on the induction of skin cancer in rats irradiated with electrons were reanalyzed and combined with results of the new experiments. Skin cancer yield versus dose for argon ions was consistent with the linear-quadratic model, but the cancer yield for electrons was considerably lower (by a factor of 6.7 at 10 Gy) than the prediction based on the linear-quadratic model. The cancer yield for electron radiation was better fitted by a dose-cubed power function than a linear-quadratic function. The results indicate a substantially lower carcinogenic effectiveness for electron radiation, especially at lower doses, in comparison to argon ions and suggest that electrons may cause cancer by a three-event pathway instead of the two-event pathway that is consistent with the results for argon ions

Previous work from this laboratory demonstrated that neonatal rats and postweanling rabbits are more sensitive to ozone-induced stimulation of pulmonary arachidonic acid (AA) metabolism than are young adults (Fundam. Appl. Toxicol. 15, 779.) In the study reported here, we have extended our initial investigation to include the influence of animal age on temporal aspects of pulmonary AA metabolism and several other responses to brief exposures to 1 ppm ozone. Rats of discrete ages ranging from 13 days to 16 weeks were exposed to 1 ppm ozone or to air for 2, 4, or 6 hr. Immediately following exposure the lungs were lavaged with six consecutive volumes of phosphate-buffered saline and the acellular fluid from the first lavage volume recovered was analyzed for its content of prostaglandin E2 (PGE2), protein, and lactate dehydrogenase. Leukocytes recovered by lavage were quantitated and characterized by viability and percentage of polymorphonuclear (PMN) cells. Several lines of evidence verified that PGE2 was produced by the lung as a consequence of ozone exposure and that its concentration in the fluid from the first lavage was a reasonably good index of pulmonary AA metabolism to prostanoids. We also demonstrated that the lavage process itself stimulates the lung, resulting in increased AA metabolism to prostanoids that were recovered in the second and following lavage volumes. The time course of PGE2 production by the ozone-exposed lung varied considerably with animal age. Neonatal rats 13 days of age were the most sensitive to ozone stimulation. At 2 hr of exposure, PGE2 concentration in the first lung lavage of these animals peaked at values approximately two orders of magnitude above controls and then decreased sharply with continued exposure. Adults and older neonates (18 days of age) were much less responsive to 2-hr exposures; however, continued exposure of these rats for up to 6 hr resulted in increasing PGE2 concentration in the first lung lavage. Other responses showed various degree of age dependence. The percentage of lavaged leukocytes that were nonviable (i.e., trypan blue-positive) showed a strong inverse correlation with animal age. In 13-day-old rats that were exposed for 6 hr, the percentage of dead leukocytes reached nearly 50%. In addition, sheets or clumps of dead cells that were judged to be epithelial cells were lavaged from these animals. Conversely, 16-week-old adult males exposed to ozone for 6 hr showed little evidence of damage to cells of the respiratory tract.(ABSTRACT TRUNCATED AT 400 WORDS)

BACKGROUND: Inadequate reproducibility of Wolfe's classification of mammographic parenchymal patterns may explain its limited use in clinical and screening practice. If the misclassification of mammographic parenchymal pattern categories is substantial, inconsistencies in study results will occur, which could at least partially explain the frequent inability to replicate Wolfe's findings in studies of breast cancer. In this article, results of a study to determine whether consensus to resolve inconsistencies between raters would improve the level of concordance in mammographic parenchymal pattern categorization and thus help reduce misclassification are presented. METHODS. One hundred consecutive mammograms from a large screening clinic in New York City were classified independently by two expert mammographers on two separate occasions, 8 days apart. Coding was repeated in two consensus conferences several weeks later. Reliability was estimated by computing intraclass correlation coefficients. RESULTS: Initially, the average intraobserver reliability for the four patterns was 0.68 and the interobserver reliability was 0.65. After consensus, reliability improved markedly to 0.88. CONCLUSION: It is concluded that the added complication and cost of consensus ratings will be more than offset by a substantial increase in precision