Impact of endocrine disruptors from mother's diet on immuno-hormonal orchestration of brain development and introduction of the virtual human twin tool.

Diet has long been known to modify physiology during development and adulthood. However, due to a growing number of manufactured contaminants and additives over the last few decades, diet has increasingly become a source of exposure to chemicals that has been associated with adverse health risks. Sources of food contaminants include the environment, crops treated with agrochemicals, inappropriate storage (e.g., mycotoxins) and migration of xenobiotics from food packaging and food production equipment. Hence, consumers are exposed to a mixture of xenobiotics, some of which are endocrine disruptors (EDs). The complex interactions between immune function and brain development and their orchestration by steroid hormones are insufficiently understood in human populations, and little is known about the impact on immune-brain interactions by transplacental fetal exposure to EDs via maternal diet. To help to identify the key data gaps, this paper aims to present (a) how transplacental EDs modify immune system and brain development, and (b) how these mechanisms may correlate with diseases such as autism and disturbances of lateral brain development. Attention is given to disturbances of the subplate, a transient structure of crucial significance in brain development. Additionally, we describe cutting edge approaches to investigate the developmental neurotoxicity of EDs, such as the application of artificial intelligence and comprehensive modelling. In the future, highly complex investigations will be performed using virtual brain models constructed using sophisticated multi-physics/multi-scale modelling strategies based on patient and synthetic data, which will enable a greater understanding of healthy or disturbed brain development.

Polychlorinated biphenyl serum concentrations, lifestyle and time-to-pregnancy.

BACKGROUND: Consumption of fish contaminated with polychlorinated biphenyls (PCBs) and prenatal PCB serum concentrations have been associated with a longer time-to-pregnancy (TTP). However, the relationship between preconception serum PCBs concentrations and TTP has not been previously studied. METHODS: Eighty-three women (contributing 442 menstrual cycles) planning pregnancies completed daily diaries regarding menstruation, intercourse, home pregnancy test results, and reported use of alcohol and cigarettes. TTP denoted the number of observed menstrual cycles required for pregnancy. Preconception blood specimens underwent toxicologic analysis for 76 PCB congeners via gas chromatography with electron capture; serum lipids were quantified with enzymatic methods. A priori, PCB congeners were summed into a total and three groupings-estrogenic, anti-estrogenic and other-and entered into discrete analogs of Cox models with time-varying covariates to estimate fecundability odds ratios (FOR) and corresponding 95% confidence intervals (CIs). RESULTS: Estrogenic and anti-estrogenic PCB concentrations (ng/g serum) conferred reduced FORs in fully adjusted models (0.32; 95% CI 0.03, 3.90 and 0.01: 95% CI < 0.00, 1.99, respectively). Reduced FORs (0.96) were observed for alcohol consumption standardized to a 28-day menstrual cycle in the same adjusted model (FOR = 0.96; 95% CI 0.93, 1.00). CONCLUSIONS: These data suggest that environmental exposures including those amenable to change, such as alcohol consumption, may impact female fecundity. The findings are sensitive to model specification and PCB groupings, underscoring the need to further assess the impact of chemical mixtures on sensitive reproductive outcomes, such as TTP, especially in the context of lifestyle factors which are amenable to change, thereby improving reproductive health.

Testes in Enchytraeus fragmentosus Bell.

Testes have been localized in the seventh or eighth segment of Enchytraeus fragmentosus Bell. This species was previously described as lacking gonads.

Erratum: Frequency of heavy vehicle traffic and association with DNA methylation at age 18 years in a subset of the Isle of Wight birth cohort.

[This corrects the article DOI: 10.1093/eep/dvy028.][This corrects the article DOI: 10.1093/eep/dvy028.].

Frequency of heavy vehicle traffic and association with DNA methylation at age 18 years in a subset of the Isle of Wight birth cohort.

Assessment of changes in DNA methylation (DNA-m) has the potential to identify adverse environmental exposures. To examine DNA-m among a subset of participants (n = 369) in the Isle of Wight birth cohort who reported variable near resident traffic frequencies. We used self-reported frequencies of heavy vehicles passing by the homes of study subjects as a proxy measure for TRAP, which were: never, seldom, 10 per day, 1-9 per hour and >10 per hour. Methylation of cytosine-phosphate-guanine (CpG) dinucleotide sequences in the DNA was assessed from blood samples collected at age 18 years (n = 369) in the F1 generation. We conducted an epigenome wide association study to examine CpGs related to the frequency of heavy vehicles passing by subjects' homes, and employed multiple linear regression models to assess potential associations. We repeated some of these analysis in the F2 generation (n = 140). Thirty-five CpG sites were associated with heavy vehicular traffic. After adjusting for confounders, we found 23 CpGs that were more methylated, and 11 CpGs that were less methylated with increasing heavy vehicular traffic frequency among all subjects. In the F2 generation, 2 of 31 CpGs were associated with traffic frequencies and the direction of the effect was the same as in the F1 subset while differential methylation of 7 of 31 CpG sites correlated with gene expression. Our findings reveal differences in DNA-m in participants who reported higher heavy vehicular traffic frequencies when compared to participants who reported lower frequencies.

Predilection of lung cancer for the upper lobes: an epidemiologic inquiry.

Data from 24,798 cases of primary neoplasm of the lung registered by the Surveillance, Epidemiology, and End Results Program between 1973 and 1977 were examined for the demographic determinants of lobe of origin. Lung cancer occurred predominantly in the upper lobes in both sexes, in both blacks and whites, and at all ages. This pattern was observed for squamous cell and small cell carcinoma as well as adenocarcinoma. The predominance of lung cancer in the upper lobes was much stronger in the young and somewhat stronger in blacks. These findings are discussed in light of current theories of pulmonary carcinogenesis. Current theories may not explain entirely these observed patterns, and further inquiries into this question, therefore, may be useful.

Premenopausal breast cancer risk and intake of vegetables, fruits, and related nutrients.

BACKGROUND: Given the international variations in breast cancer incidence rates and the changes in breast cancer incidence among migrant populations, it has been hypothesized that diet is a factor influencing risk of this disease. Many studies indicate that a diet high in vegetables and fruits may protect against breast cancer. PURPOSE: We conducted a case-control study of diet, including the intake of non-food supplements, and premenopausal breast cancer risk. We evaluated in detail usual intake of vegetables and fruits (each measured as the total reported grams consumed for all queried vegetables and fruit), vitamins C and E, folic acid, individual carotenoids, and dietary fiber with its components. METHODS: Case patients (n=297) were identified through pathology records from hospitals in Erie and Niagara counties in western New York. They consisted of premenopausal women 40 years of age or oder who were diagnosed with breast cancer from November 1986 through April 1991. Control subjects (n=311), frequency-matched to case patients on the basis of age and county of residence, were randomly selected from New York State Department of Motor Vehicles records. In-person interviews included detailed reports of usual diet in the period 2 years before the interview. Unconditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: There was a reduction in risk associated with high intake of several nutrients. With the lowest quartile of intake as the referent, adjusted ORs for the highest quartile of intake for specific nutrients were as follows: vitamin C (OR=0.53; 95% CI=0.33-0.86), alpha-tocopheral (OR=0.55; 95% CI=0.34-0.88), folic acid (OR=0.50; 95% CI=0.31-0.82), alpha-carotene (OR=0.67; 95% CI=0.42-1.08) and beta-carotene (OR=0.46; 95% CI=0.28-0.74), lutein + zeaxanthin (OR=0.47; 95% CI=0.28.0-77), and dietary fiber from vegetables and fruits (OR=0.48; 95% CI=0.30-0.78). No association with risk was found for beta-cryptoxanthin, lycopene, or grain fiber. Fruits were weakly associated with a reduction in risk (fourth quartile OR=0.67; 95% CI=0.42-1.09). No association was found between breast cancer risk and intake of vitamins C and E and folic acid taken as supplements. A strong inverse association between total vegetable intake and risk was observed (fourth quartile OR=0.46; 95% CI=0.28-0.74). This inverse association was found to be independent of vitamin C,alpha-tocopherol, folic acid, dietary fiber, and alpha-carotene. Adjusting for beta-carotene or lutein + zeaxanthin somewhat attenuated the inverse association with vegetable intake. CONCLUSIONS: In this population, intake of vegetables appears to decrease premenopausal breast cancer risk. This effect may be related, in part, to beta-carotene and lutein + zeaxanthin in vegetables. It appears, however, that, of the nutrients and food components examined, no single dietary factor explains the effect. Evaluated components found together in vegetables may have a synergistic effect on breast cancer risk; alternatively, other unmeasured factors in these foods may also influence risk.

Cytochrome P4501A1 and glutathione S-transferase (M1) genetic polymorphisms and postmenopausal breast cancer risk.

Polycyclic aromatic hydrocarbons, possible human breast carcinogens, are metabolized by cytochrome P4501A1 (CYP1A1) and glutathione S-transferase (GSTM1). A CYP1A1 polymorphism (isoleucine to valine substitution in exon 7) or the null allele for GSTM1 may affect the mutagenic potential of polycyclic aromatic hydrocarbons. We examined polymorphisms in GSTM1 and CYP1A1 in relation to breast cancer risk. Included were 216 postmenopausal Caucasian women with incident breast cancer and 282 community controls. DNA analyses suggested no increased breast cancer risk with the null GSTM1 genotype [odds ratio (OR) = 1.10; CI, 0.73-1.64], although there was some indication that the null genotype was associated with risk among the youngest postmenopausal women (OR = 2.44; CI, 0.89-6.64). Slightly elevated risk was associated with the CYP1A1 polymorphism (OR = 1.61; CI, 0.94-2.75) and was highest for those who smoked up to 29 pack-years (OR = 5.22; CI, 1.16-23.56). Statistical power to detect an effect may be limited by small numbers, and larger sample sizes would be required to corroborate these suggestive findings.

Manganese superoxide dismutase (MnSOD) genetic polymorphisms, dietary antioxidants, and risk of breast cancer.

Oxidative stress, resulting from the imbalance between prooxidant and antioxidant states, damages DNA, proteins, cell membranes, and mitochondria and seems to play a role in human breast carcinogenesis. Dietary sources of antioxidants (chemical) and endogenous antioxidants (enzymatic), including the polymorphic manganese superoxide dismutase (MnSOD), can act to reduce the load of oxidative stress. We hypothesized that the valine-to-alanine substitution that seems to alter transport of the enzyme into the mitochondrion, changing its efficacy in fighting oxidative stress, was associated with breast cancer risk and that a diet rich in sources of antioxidants could ameliorate the effects on risk. Data were collected in a case-control study of diet and breast cancer in western New York from 1986 to 1991. Caucasian women with incident, primary, histologically confirmed breast cancer were frequency-matched on age and county of residence to community controls. Blood specimens were collected and processed from a subset of participants in the study (266 cases and 295 controls). Using a RFLP that distinguishes a valine (V) to alanine (A) change in the -9 position in the signal sequence of the protein for MnSOD, we characterized MnSOD genotypes in relation to breast cancer risk. We also evaluated the effect of the polymorphism on risk among low and high consumers of fruits and vegetables. Premenopausal women who were homozygous for the A allele had a 4-fold increase in breast cancer risk in comparison to those with 1 or 2 V alleles (odds ratio, 4.3; 95% confidence interval, 1.7-10.8). Risk was most pronounced among women below the median consumption of fruits and vegetables and of dietary ascorbic acid and alpha-tocopherol, with little increased risk for those with diets rich in these foods. Relationships were weaker among postmenopausal women, although the MnSOD AA genotype was associated with an almost 2-fold increase in risk (odds ratio, 1.8; confidence interval, 0.9-3.6). No appreciable modification of risk by diet was detected for these older women. These data support the hypothesis that MnSOD and oxidative stress play a significant role in breast cancer risk, particularly in premenopausal women. The finding that risk was greatest among women who consumed lower amounts of dietary antioxidants and was minimal among high consumers indicates that a diet rich in sources of antioxidants may minimize the deleterious effects of the MnSOD polymorphism, thereby supporting public health recommendations for the consumption of diets rich in fruits and vegetables as a preventive measure against cancer.

Genetic polymorphisms in catechol-O-methyltransferase, menopausal status, and breast cancer risk.

Polymorphic catechol-O-methyltransferase (COMT) catalyzes the O-methylation of estrogen catechols. In a case-control study, we evaluated the association of the low-activity allele (COMT(Met)) with breast cancer risk. Compared to women with COMT(Val/Val), COMT(Met/Met) was associated with an increased risk among premenopausal women [odds ratio (OR), 2.1; confidence interval (CI), 1.4-4.3] but was inversely associated with postmenopausal risk (OR, 0.4; CI, 0.2-0.7). The association of risk with at least one low-activity COMT(Met) allele was strongest among the heaviest premenopausal women (OR, 5.7; CI, 1.1-30.1) and among the leanest postmenopausal women (OR, 0.3; CI, 0.1-0.7), suggesting that COMT, mediated by body mass index, may be playing differential roles in human breast carcinogenesis, dependent upon menopausal status.

Alcohol consumption and lung cancer: a review of the epidemiologic evidence.

A role for alcohol consumption in lung cancer etiology has been suggested in some studies, but this possible relationship has been often regarded with skepticism, with any indication of an association being attributed to confounding by cigarette smoking. The purpose of this work was to review the epidemiological evidence for an association of alcohol and lung cancer and to identify gaps in that research. The studies reviewed here provide some indication that alcohol and particularly beer intake may increase lung cancer risk after controlling for cigarette smoking. Although the evidence is not conclusive, it warrants additional consideration of alcohol as a risk factor in lung cancer etiology, independent of cigarette smoking. Recommendations for future studies are provided.

Environmental organochlorine exposure and postmenopausal breast cancer risk.

Environmental exposure to organochlorine compounds has been associated with a potential role in breast cancer etiology, but results from previous investigations yielded inconsistent results. In this case-control study, we examined the effect of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), hexachlorobenzene (HCB), mirex, and several measures of polychlorinated biphenyls (PCBs) on postmenopausal breast cancer risk. The study sample included 154 primary, incident, histologically confirmed, postmenopausal breast cancer cases and 192 postmenopausal community controls. Usual diet, reproductive and medical histories, and other lifestyle information was obtained by an extensive in person interview. Serum levels (ng/g) of DDE, HCB, mirex, and 73 PCB congeners were determined by gas chromatography with electron capture. PCB exposure was examined as total measured PCB levels, total number of detected PCB peaks, and three PCB congener groups. In the total sample, there was no evidence of an adverse effect of serum levels of DDE [odds ratio (OR), 1.34; 95% confidence interval (CI) 0.71-2.55], HCB (OR, 0.81; 95% CI, 0.43-1.53), or mirex (OR, 1.37; 95% CI, 0.78-2.39). Further, higher serum levels of total PCBs (OR, 1.14; 95% CI, 0.61-2.15), moderately chlorinated PCBs (OR, 1.37; 95% CI, 0.73-2.59), more highly chlorinated PCBs (OR, 1.19; 95% CI, 0.60-2.36), or greater number of detected peaks (OR, 1.34; 95% CI, 0.72-2.47) were not associated with increased risk. There was some indication of a modest increase in risk for women with detectable levels of less chlorinated PCBs (OR, 1.66; 95% CI, 1.07-2.88). Among parous women who had never lactated, there was some evidence for increased risk, associated with having detectable levels of mirex (OR, 2.42; 95% CI, 0.98-4.32), higher serum concentrations of total PCBs (OR, 2.87; 95% CI, 1.01-7.29), moderately chlorinated PCBs (OR, 3.57; 95% CI, 1.10-8.60), and greater numbers of detected PCB congeners (OR, 3.31; 95% CI, 1.04-11.3). These results suggest that an increase in risk of postmenopausal breast cancer associated with environmental exposure to PCBs and mirex, if at all present, is restricted to parous women who had never breast-fed an infant. Future studies should consider lactation history of participants, as well as use similar epidemiological and laboratory methodologies, to ensure comparability of results across studies.

Polychlorinated biphenyls, cytochrome P4501A1 polymorphism, and postmenopausal breast cancer risk.

In experimental systems, polychlorinated biphenyls (PCBs) induce cytochrome P4501A1 (CYP1A1), which is involved in metabolism of steroid hormones and polycyclic aromatic hydrocarbons in humans. A genetic polymorphism coding for a valine to isoleucine substitution in exon 7 has been associated with lung cancer risk in Japanese populations. In a previous study, we found no association between CYP1A1 genotype and breast cancer risk. However, we were interested in determining whether genotype would relate to risk when PCB body burden was taken into account. In a subset of a case-control study in western New York, 154 postmenopausal women with incident, primary, histologically confirmed postmenopausal breast cancer and 192 community controls were interviewed and underwent phlebotomy. Serum levels of 56 PCB peaks were determined by high resolution gas chromatography with electron capture. PCR-RFLP analyses of the CYP1A1 polymorphism were performed. Unconditional logistic regression was used to compute adjusted odds ratios and 95% confidence intervals. Among women with serum PCB levels above the median of the distribution in the control group, there was increased risk of breast cancer associated with the presence of at least one valine allele, compared with women who were homozygous for the isoleucine alleles (odds ratio, 2.93; 95% confidence interval, 1.17-7.36). Among women with low PCB body burden, no association between CYP1A1 genotype and breast cancer risk was observed. Adjustment for serum lipids and body mass index did not affect the magnitude of the observed associations. PCB body burden may modify the effect of the polymorphism on postmenopausal breast cancer risk through increased CYP1A1 enzyme induction or by activation by specific PCB congeners. These results should be considered preliminary, pending replication by other studies.

Coffee, cigarette smoking, and bladder cancer in western New York.

The association between consumption of coffee and bladder cancer and the effect modification of cigarette smoking was investigated as part of a comprehensive case-control study. The study population consisted of 351 case patients with histologically confirmed transitional cell carcinomas of the bladder among white males and 855 white male control subjects selected from Erie, Niagara, and Monroe counties in New York from 1979 to 1985. Usual diet, coffee consumption, and cigarette use were estimated by comprehensive interviews using a detailed food frequency questionnaire. After adjustment for age, education, and dietary risk factors by multiple logistic regression, risk was found to increase with increasing pack-years of cigarette use with an odds ratio in the highest quartile of 2.7 (95% confidence interval, 1.8 to 4.0) when compared to the lowest quartile. Coffee consumption was associated with an increased risk for bladder cancer among the heaviest coffee drinkers after adjustment for cigarette smoking and other dietary risk factors (odds ratio, 2.1; 95% confidence interval, 1.3 to 3.2). The effect was more pronounced among nonsmokers, especially among those 65 years and older. These findings support the contention that coffee is a weak carcinogen.

Exercise, occupational activity, and risk of endometrial cancer.

We conducted a case-control study in western New York state among 232 women with newly-diagnosed endometrial cancer and 631 controls selected from the community. Physical activity was measured by participation in vigorous exercise and walking at four time periods: at age 16, and at 20, 10, and 2 years before the interview and by occupational activity based on a detailed lifetime history. Women who did a moderate amount of vigorous exercise at age 16 and at 20 years before the interview were at reduced risk as compared with those who reported no activity, with odds ratios (OR) (95% confidence intervals) of 0.51 (0.31-0.83) and 0.50 (0.29-0.89), respectively. However, there was no evidence of declining risk with greater amount of activity. At later times, 10 years and 2 years before the interview, being in the highest group with regard to vigorous activity was associated with a slightly but nor significant lower risk as compared with women who reported no activity; the adjusted OR were 0.72 (0.43-1.19) and 0.67 (0.42-1.09), respectively. Being in the highest category of miles walked at age 16 (i.e., > or = 15 miles per week) was associated with a slightly reduced risk as compared with not walking at all (OR 0.64 (0.26-1.16)), whereas the number of miles walked at other times was not related to reduced risk. Occupational physical activity was not related to the risk of endometrial cancer. Overall, these results indicate that physical activity at levels prevalent in this population has at most a modest relationship to reduced risk of endometrial cancer.

Work and leisure time physical activity and mortality in men and women from a general population sample.

PURPOSE: The purpose of this study was to examine the long-term relationships between total physical activity and mortality from all causes and coronary heart disease (CHD) in the general population. METHODS: A prospective design was used, following participants for 29 years, beginning in 1960. The study population consisted of a randomly selected sample of white male (n = 698) and female (n = 763) residents of Buffalo, New York with a 79.0% participation rate and follow-up rates of 96.0% and 90.2% in males and females, respectively. At baseline, comprehensive information was obtained regarding participants' usual physical activity at work and during leisure time. RESULTS: As of December 31, 1989, three hundred and two (43.3%) men and 276 (41.0%) women died, 109 (15.6%) and 81 (10.6%) from CHD, respectively. In men, a significant interaction was found between activity and body mass index (BMI) for both outcomes. In women, a significant activity by age interaction was observed. In non-obese men (BMI<27.02), activity was inversely associated with all-cause [relative risk (RR) = 0.59; 95% confidence interval (CI), 0.39-0.89] and CHD mortality (RR = 0.39; 95% CI, 0.18-0.83), independent from the effects of age and education. No such associations were found in obese men and increased risks could not be ruled out. Among women, younger participants (age <60 years) had a significantly reduced risk of CHD death with increased activity (RR = 0.26; 95% CI, 0.07-0.99). No other significant associations were observed. CONCLUSIONS: Physical activity favorably influences mortality risks in non-obese men and younger women. Gender-specific factors should be considered for potential effect modification.

Consumption of PCB-contaminated sport fish and risk of spontaneous fetal death.

Spontaneous fetal death has been observed among various mammalian species after exposure to polychlorinated biphenyls (PCBs). Our exposure-based cohort study assessed the relationship between consumption of PCB-contaminated Lake Ontario sport fish and spontaneous fetal death using 1820 multigravid fertile women from the 1990-1991 New York State Angler Cohort Study. Fish consumption data were obtained from food frequency questionnaires and history of spontaneous fetal death from live birth certificates. Analyses were stratified by number of prior pregnancies and controlled for smoking and maternal age. No significant increases in risk for fetal death were observed across four measures of exposure: a lifetime estimate of PCB exposure based on species-specific PCB levels; the number of years of fish consumption; kilograms of sport fish consumed in 1990-1991; and a lifetime estimate of kilograms eaten. A slight risk reduction was seen for women with two prior pregnancies at the highest level of PCB exposure (odds ratio = 0.36; 95% CI, 0.14-0.92) and for women with three or more prior pregnancies with increasing years of fish consumption (odds ratio = 0.97; 95% CI, 0.94-0.99). These findings suggest that consumption of PCB-contaminated sport fish does not increase the risk of spontaneous fetal death.

Exposure to dioxin and nonneoplastic mortality in the expanded IARC international cohort study of phenoxy herbicide and chlorophenol production workers and sprayers.

The authors studied noncancer mortality among phenoxyacid herbicide and chlorophenol production workers and sprayers included in an international study comprising 36 cohorts from 12 countries followed from 1939 to 1992. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin or higher chlorinated dioxins (TCDD/HCD) was discerned from job records and company questionnaires with validation by biologic and environmental measures. Standard mortality ratio analyses suggested a moderate healthy worker effect for all circulatory diseases, especially ischemic heart disease, among both those exposed and those not exposed to TCDD/HCD. In Poisson regression analyses, exposure to TCDD/HCD was not associated with increased mortality from cerebrovascular disease. However, an increased risk for circulatory disease, especially ischemic heart disease (rate ratio [RR] 1.67, 95% confidence interval [Cl] 1.23-2.26) and possibly diabetes (RR 2.25, 95% Cl 0.53-9.50), was present among TCDD/HCD-exposed workers. Risks tended to be higher 10 to 19 years after first exposure and for those exposed for a duration of 10 to 19 years. Mortality from suicide was comparable to that for the general population for all workers exposed to herbicides or chlorophenols and was associated with short latency and duration of exposure. More refined investigations of the ischemic heart disease and TCDD/HCD exposure association are warranted.

Women in the public sector: cancer mortality.

Very few mortality occupational studies of female workers have been published, even though the number of women in the workforce has increased dramatically to reach more than 45%. Public sector employees comprise 12% of the female workforce. This article reports the findings of a retrospective cohort mortality study of 1371 full-time female employees of the city of Buffalo, New York, who were employed between January 1, 1950, and October 1, 1979, and have worked a minimum of 5 years. The majority of women were hired in the 1940s and early 1950s and began employment after age 30. This predominantly white-collar, service-oriented female cohort demonstrated significantly lower all-cause mortality than that expected based on US mortality rates for white females. The highest observed numbers of cancer deaths were for breast, digestive, and respiratory cancers. The majority of person-years were accrued in clerical and service occupations. Higher-than-expected mortality was shown for reproductive and respiratory cancers among professional employees; digestive cancers, diseases of the nervous system, and pneumonia among clerical workers; and cancers of the lung and brain and diseases of the digestive system, especially ulcers, among service employees. Because these results are based on few observed cases, they must be interpreted cautiously.

Risk of premenopausal breast cancer in association with occupational exposure to polycyclic aromatic hydrocarbons and benzene.

OBJECTIVES: This study examined the relationship between risk of premenopausal breast cancer and occupational exposure to benzene and polycyclic aromatic hydrocarbons (PAH) and whether the proposed relationship between PAH and breast cancer differed by tumor estrogen receptor (ER) status. METHODS: In a case-referent study of premenopausal breast cancer, occupational histories and other information were obtained through interviews, and job-exposure matrices were used to assess exposure to PAH and benzene. RESULTS: A dose-response relationship for the probability of exposure to benzene [low: odds ratio (OR) 1.64, 95% confidence interval (95% CI) 0.64-4.21; high: OR 1.95, 95% CI 1.14-3.33) and to PAH (low: OR 1.56, 95% CI 0.78-3.12; high: OR 2.40, 95% CI 0.96-6.01). Risk increased with duration of exposure to benzene, but not to PAH. A dose-response relationship was not evident for the intensity of exposure to benzene or to PAH. When analyses were stratified by tumor ER status, PAH exposure was related to a greater increase in the risk of ER-positive (OR 2.27, 95% CI 1.14-4.54) than ER-negative (OR 1.12, 95% CI 0.47-2.64) breast cancer. Risk of ER-positive, but not ER-negative, tumors increased with the probability of exposure to PAH. CONCLUSIONS: The findings suggest an association between risk and occupational exposure to benzene. Although it was difficult to study PAH independently of benzene, there was some suggestion of an association between PAH exposure and ER-positive tumors. These data should be interpreted with caution because of the limitations of this study, including low-response rates and small numbers of exposed persons.