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1.  The Upper Midwest Health Study: gliomas and occupational exposure to chlorinated solvents 
Occupational exposure to chlorinated aliphatic solvents has been associated with an increased cancer risk, including brain cancer. However, many of these solvents remain in active, large-volume use. We evaluated glioma risk from non-farm occupational exposure (ever/never and estimated cumulative exposure) to any of the six chlorinated solvents—carbon tetrachloride, chloroform, methylene chloride, trichloroethylene, tetrachloroethylene or 1,1,1-trichloroethane—among 798 cases and 1175 population-based controls, aged 18–80 years and non-metropolitan residents of Iowa, Michigan, Minnesota and Wisconsin.
Solvent use was estimated based on occupation, industry and era, using a bibliographic database of published exposure levels and exposure determinants. Unconditional logistic regression was used to calculate ORs adjusted for frequency matching variables age group and sex, and age and education. Additional analyses were limited to 904 participants who donated blood specimens (excluding controls reporting a previous diagnosis of cancer) genotyped for glutathione-S-transferases GSTP1, GSTM3 and GSTT1. Individuals with functional GST genes might convert chlorinated solvents crossing the blood–brain barrier into cytotoxic metabolites.
Both estimated cumulative exposure (ppm-years) and ever exposure to chlorinated solvents were associated with decreased glioma risk and were statistically significant overall and for women. In analyses comparing participants with a high probability of exposure with the unexposed, no associations were statistically significant. Solvent-exposed participants with functional GST genes were not at increased risk of glioma.
We observed no associations of glioma risk and chlorinated solvent exposure. Large pooled studies are needed to explore the interaction of genetic pathways and environmental and occupational exposures in glioma aetiology.
PMCID: PMC4563805  PMID: 23104734
2.  Evaluation of cumulative PCB exposure estimated by a job exposure matrix versus PCB serum concentrations 
Although polychlorinated biphenyls (PCBs) have been banned in many countries for more than three decades, exposures to PCBs continue to be of concern due to their long half-lives and carcinogenic effects. In National Institute for Occupational Safety and Health studies, we are using semiquantitative plant-specific job exposure matrices (JEMs) to estimate historical PCB exposures for workers (n=24,865) exposed to PCBs from 1938 to 1978 at three capacitor manufacturing plants. A subcohort of these workers (n=410) employed in two of these plants had serum PCB concentrations measured at up to four times between 1976 and 1989. Our objectives were to evaluate the strength of association between an individual worker’s measured serum PCB levels and the same worker’s cumulative exposure estimated through 1977 with the (1) JEM and (2) duration of employment, and to calculate the explained variance the JEM provides for serum PCB levels using (3) simple linear regression. Consistent strong and statistically significant associations were observed between the cumulative exposures estimated with the JEM and serum PCB concentrations for all years. The strength of association between duration of employment and serum PCBs was good for highly chlorinated (Aroclor 1254/HPCB) but not less chlorinated (Aroclor 1242/LPCB) PCBs. In the simple regression models, cumulative occupational exposure estimated using the JEMs explained 14–24 % of the variance of the Aroclor 1242/LPCB and 22–39 % for Aroclor 1254/HPCB serum concentrations. We regard the cumulative exposure estimated with the JEM as a better estimate of PCB body burdens than serum concentrations quantified as Aroclor 1242/LPCB and Aroclor 1254/HPCB.
PMCID: PMC4557726  PMID: 23475397
Polychlorinated biphenyls; PCB; Serum PCB; Aroclor; Occupational exposure
3.  Historical reconstruction of polychlorinated biphenyl (PCB) exposures for workers in a capacitor manufacturing plant 
We developed a semiquantitative job exposure matrix (JEM) for workers exposed to polychlorinated biphenyls (PCBs) at a capacitor manufacturing plant from 1946 to 1977. In a recently updated mortality study, mortality of prostate and stomach cancer increased with increasing levels of cumulative exposure estimated with this JEM (trend p values=0.003 and 0.04, respectively). Capacitor manufacturing began with winding bales of foil and paper film, which were placed in a metal capacitor box (pre-assembly), and placed in a vacuum chamber for flood-filling (impregnation) with dielectric fluid (PCBs). Capacitors dripping with PCB residues were then transported to sealing stations where ports were soldered shut before degreasing, leak testing, and painting. Using a systematic approach, all 509 unique jobs identified in the work histories were rated by predetermined process- and plant-specific exposure determinants; then categorized based on the jobs’ similarities (combination of exposure determinants) into 35 job exposure categories. The job exposure categories were ranked followed by a qualitative PCB exposure rating (baseline, low, medium, and high) for inhalation and dermal intensity. Category differences in other chemical exposures (solvents, etc.) prevented further combining of categories. The mean of all available PCB concentrations (1975 and 1977) for jobs within each intensity rating was regarded as a representative value for that intensity level. Inhalation (in microgram per cubic milligram) and dermal (unitless) exposures were regarded as equally important. Intensity was frequency adjusted for jobs with continuous or intermittent PCB exposures. Era-modifying factors were applied to the earlier time periods (1946–1974) because exposures were considered to have been greater than in later eras (1975–1977). Such interpolations, extrapolations, and modifying factors may introduce non-differential misclassification; however, we do believe our rigorous method minimized misclassification, as shown by the significant exposure–response trends in the epidemiologic analysis.
PMCID: PMC4557729  PMID: 23475444
Polychlorinated biphenyls (PCB); Job exposure matrix (JEM)
4.  Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Congenital Heart Defects among Offspring in the National Birth Defects Prevention Study 
There is evidence in experimental model systems that exposure to polycyclic aromatic hydrocarbons (PAHs) results in congenital heart defects (CHDs); however, to our knowledge, this relationship has not been examined in humans. Therefore, we conducted a case-control study assessing the association between estimated maternal occupational exposure to PAHs and CHDs in offspring.
Data on CHD cases and control infants were obtained from the National Birth Defects Prevention Study for the period of 1997 to 2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to evaluate the association between maternal occupational PAH exposure and specific CHD phenotypic subtypes among offspring.
The prevalence of occupational PAH exposure was 4.0% in CHD case mothers (76/1907) and 3.6% in control mothers (104/2853). After adjusting for maternal age, race or ethnicity, education, smoking, folic acid supplementation, and study center, exposure was not associated with conotruncal defects (adjusted odds ratio [AOR], 0.98; 95% confidence interval [CI], 0.58–1.67), septal defects (AOR, 1.28; 95% CI, 0.86–1.90), or with any isolated CHD subtype.
Our findings do not support an association between potential maternal occupational exposure to PAHs and various CHDs in a large, population-based study. For CHD phenotypic subtypes in which modest nonsignificant associations were observed, future investigations could be improved by studying populations with a higher prevalence of PAH exposure and by incorporating information on maternal and fetal genotypes related to PAH metabolism.
PMCID: PMC4552186  PMID: 22945317
birth defects; congenital heart defects; epidemiology; maternal occupation; polycyclic aromatic hydrocarbons
5.  The Upper Midwest Health Study: Industry and Occupation of Glioma Cases and Controls 
Understanding glioma etiology requires determining which environmental factors are associated with glioma. Upper Midwest Health Study case–control participant work histories collected 1995–1998 were evaluated for occupational associations with glioma. “Exposures of interest” from our study protocol comprise our a priori hypotheses.
Materials and Methods
Year-long or longer jobs for 1,973 participants were assigned Standard Occupational Classifications (SOC) and Standard Industrial Classifications (SIC). The analysis file includes 8,078 SIC- and SOC-coded jobs. For each individual, SAS 9.2 programs collated employment with identical SIC-SOC coding. Distributions of longest “total employment duration” (total years worked in jobs with identical industry and occupation codes, including multiple jobs, and non-consecutive jobs) were compared between cases and controls, using an industrial hygiene algorithm to group occupations.
Longest employment duration was calculated for 780 cases and 1,156 controls. More case than control longest total employment duration was in the “engineer, architect” occupational group [16 cases, 10 controls, odds ratio (OR) 2.50, adjusted for age group, sex, age and education, 95% confidence interval (CI) 1.12–5.60]. Employment as a food processing worker [mostly butchers and meat cutters] was of borderline significance (27 cases, 21 controls, adjusted OR: 1.78, CI: 0.99–3.18).
Among our exposures of interest work as engineers or as butchers and meat cutters was associated with increased glioma risk. Significant associations could be due to chance, because of multiple comparisons, but similar findings have been reported for other glioma studies. Our results suggest some possible associations but by themselves could not provide conclusive evidence.
PMCID: PMC4530494  PMID: 22715102
glioma; case–control studies; occupation; industry; occupational exposure
6.  Maternal occupational exposure to polycyclic aromatic hydrocarbons and small for gestational age offspring 
While some of the highest maternal exposures to polycyclic aromatic hydrocarbons (PAHs) occur in the workplace, there is only one previous study of occupational PAH exposure and adverse pregnancy outcomes. We sought to extend this literature using interview data combined with detailed exposure assessment.
Data for 1997–2002 were analysed from mothers of infants without major birth defects in the National Birth Defects Prevention Study, a large population-based case-control study in the USA. Maternal telephone interviews yielded information on jobs held in the month before conception through delivery. From 6252 eligible control mothers, 2803 completed the interview, had a job, met other selection criteria, and were included in the analysis. Two industrial hygienists independently assessed occupational exposure to PAHs from the interview and reviewed results with a third to reach consensus. Small for gestational age (SGA) was the only adverse pregnancy outcome with enough exposed cases to yield meaningful results. Logistic regression estimated crude and adjusted ORs.
Of the 2803 mothers, 221 (7.9%) had infants who were SGA. Occupational PAH exposure was found for 17 (7.7%) of the mothers with SGA offspring and 102 (4.0%) of the remaining mothers. Almost half the jobs with exposure were related to food preparation and serving. After adjustment for maternal age, there was a significant association of occupational exposure with SGA (OR=2.2, 95% CI 1.3 to 3.8).
Maternal occupational exposure to PAHs was found to be associated with increased risk of SGA offspring.
PMCID: PMC4497781  PMID: 24893704
7.  Personal history of diabetes, genetic susceptibility to diabetes, and risk of brain glioma: a pooled analysis of observational studies 
Brain glioma is a relatively rare and fatal malignancy in adulthood with few known risk factors. Some observational studies have reported inverse associations between diabetes and subsequent glioma risk, but possible mechanisms are unclear.
We conducted a pooled analysis of original data from five nested case-control studies and two case-control studies from the U.S. and China that included 962 glioma cases and 2,195 controls. We examined self-reported diabetes history in relation to glioma risk, as well as effect modification by seven glioma risk-associated single-nucleotide polymorphisms (SNPs). We also examined the associations between 13 diabetes risk-associated SNPs, identified from genome-wide association studies, and glioma risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable-adjusted logistic regression models.
We observed a 42% reduced risk of glioma for individuals with a history of diabetes (OR=0.58, 95% CI: 0.40–0.84). The association did not differ by sex, study design, or after restricting to glioblastoma, the most common histological sub-type. We did not observe any significant per-allele trends among the 13 diabetes-related SNPs examined in relation to glioma risk.
These results support an inverse association between diabetes history and glioma risk. The role of genetic susceptibility to diabetes cannot be excluded, and should be pursued in future studies together with other factors that might be responsible for the diabetes-glioma association.
These data suggest the need for studies that can evaluate, separately, the association between type 1 and type 2 diabetes and subsequent risk of adult glioma.
PMCID: PMC3947107  PMID: 24220915
diabetes mellitus; brain cancer; glioma; cancer; epidemiology
Evaluate whether there is an association between maternal occupational exposure to polycyclic aromatic hydrocarbons (PAHs) and oral cleftsin offspring. This is the first human study of PAHs and clefts of which the authors are aware.
Case-control study.
Setting, Participants
Data for 1997–2002 from the National Birth Defects Prevention Study, a large population-based case-control study in the US, were analyzed. Maternal telephone interviews yielded information on jobs held in the month before through three months after conception. Two industrial hygienists independently assessed occupational exposure to PAHs ; all jobs rated as exposed or with rating difficulty were reviewed with a third industrial hygienist to reach consensus on all exposure parameters. Logistic regression estimated crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for cleft lip with or without cleft palate (CL±P) and cleft palate alone (CP).
There were 2989 controls( 3.5% exposed), 805 cases of CL±P (5.8% exposed) and 439 cases of CP (4.6% exposed). The odds of maternal occupational exposure to PAH (any vs none) during pregnancy was increased for CL±P cases as compared with controls (OR 1.69, 95% CI 1.18–2.40); the OR was 1.47 (95% CI 1.02–2.12) adjusted for maternal education. There was a statistically significant adjusted exposure-response relationship for CL±P (ptrend = 0.02). ORs for CP were not statistically significant.
Maternal occupational exposure to PAHs was associated with increased risk of cleft lip with or without cleft palate in offspring.
PMCID: PMC4096036  PMID: 23136939
PAHs; polycyclic aromatic hydrocarbons; occupation; malformations; oral clefts
9.  Occupational Exposure to Pesticides and Risk of Adult Brain Tumors 
American journal of epidemiology  2008;167(8):976-985.
The authors examined incident glioma and meningioma risk associated with occupational exposure to insecticides and herbicides in a hospital-based, case-control study of brain cancer. Cases were 462 glioma and 195 meningioma patients diagnosed between 1994 and 1998 in three US hospitals. Controls were 765 patients admitted to the same hospitals for nonmalignant conditions. Occupational histories were collected during personal interviews. Exposure to pesticides was estimated by use of a questionnaire, combined with pesticide measurement data abstracted from published sources. Using logistic regression models, the authors found no association between insecticide and herbicide exposures and risk for glioma and meningioma. There was no association between glioma and exposure to insecticides or herbicides, in men or women. Women who reported ever using herbicides had a significantly increased risk for meningioma compared with women who never used herbicides (odds ratio = 2.4, 95% confidence interval: 1.4, 4.3), and there were significant trends of increasing risk with increasing years of herbicide exposure (p = 0.01) and increasing cumulative exposure (p = 0.01). There was no association between meningioma and herbicide or insecticide exposure among men. These findings highlight the need to go beyond job title to elucidate potential carcinogenic exposures within different occupations.
PMCID: PMC3967588  PMID: 18299277
10.  Occupational exposure to chlorinated solvents and risks of glioma and meningioma in adults 
Occupational and environmental medicine  2012;69(11):10.1136/oemed-2012-100742.
Chlorinated solvents are classified as probable or possible carcinogens. It is unknown whether exposure to these agents increases the risk of malignant or benign brain tumors. Our objective was to evaluate associations of brain tumor risk with occupational exposure to six chlorinated solvents [i.e., dichloromethane, chloroform, carbon tetrachloride, 1,1,1-trichloroethane, trichloroethylene, and perchloroethylene].
489 glioma cases, 197 meningioma cases, and 799 controls were enrolled in a hospital-based case-control study conducted at three U.S. hospitals in Arizona, Massachusetts and Pennsylvania. Information about occupational history was obtained through a detailed in-person interview that included job-specific modules of questions such that the interview was tailored to each individual’s particular work history. An industrial hygienist assessed potential solvent exposure based on this information and an exhaustive review of the relevant industrial hygiene literature. Unconditional logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals (95%CI) for each solvent for ever/never, duration, cumulative, average weekly, and highest exposure.
Overall, we found no consistent evidence of an increased risk of glioma or meningioma related to occupational exposure to the six chlorinated solvents evaluated. There was some suggestion of an association between carbon tetrachloride and glioma in analyses restricted to exposed subjects, with average weekly exposure above the median associated with increased risk compared to below-median exposure (OR=7.1, 95%CI: 1.1, 45.2).
We found no consistent evidence for increased brain tumor risk related to chlorinated solvents.
PMCID: PMC3850418  PMID: 22864249
epidemiology; cancer; solvents
11.  Association between adult height, genetic susceptibility and risk of glioma 
Background Some, but not all, observational studies have suggested that taller stature is associated with a significant increased risk of glioma. In a pooled analysis of observational studies, we investigated the strength and consistency of this association, overall and for major sub-types, and investigated effect modification by genetic susceptibility to the disease.
Methods We standardized and combined individual-level data on 1354 cases and 4734 control subjects from 13 prospective and 2 case–control studies. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) for glioma and glioma sub-types were estimated using logistic regression models stratified by sex and adjusted for birth cohort and study. Pooled ORs were additionally estimated after stratifying the models according to seven recently identified glioma-related genetic variants.
Results Among men, we found a positive association between height and glioma risk (≥190 vs 170–174 cm, pooled OR = 1.70, 95% CI: 1.11–2.61; P-trend = 0.01), which was slightly stronger after restricting to cases with glioblastoma (pooled OR = 1.99, 95% CI: 1.17–3.38; P-trend = 0.02). Among women, these associations were less clear (≥175 vs 160–164 cm, pooled OR for glioma = 1.06, 95% CI: 0.70–1.62; P-trend = 0.22; pooled OR for glioblastoma = 1.36, 95% CI: 0.77–2.39; P-trend = 0.04). In general, we did not observe evidence of effect modification by glioma-related genotypes on the association between height and glioma risk.
Conclusion An association of taller adult stature with glioma, particularly for men and stronger for glioblastoma, should be investigated further to clarify the role of environmental and genetic determinants of height in the etiology of this disease.
PMCID: PMC3429876  PMID: 22933650
Height; brain cancer; glioma; cancer; epidemiology
12.  Maternal occupational exposure to organic solvents during early pregnancy and risks of neural tube defects and orofacial clefts 
Though toxicological experiments demonstrate the teratogenicity of organic solvents in animal models, epidemiologic studies have reported inconsistent results. Using data from the population-based National Birth Defects Prevention Study, we examined the relation between maternal occupational exposure to aromatic solvents, chlorinated solvents and Stoddard solvent during early pregnancy and neural tube defects (NTDs) and orofacial clefts (OFCs).
Cases of NTDs (anencephaly, spina bifida and encephalocele) and OFCs (cleft lip ± cleft palate and cleft palate alone) delivered between 1997 and 2002 were identified by birth defect surveillance registries in 8 states; non-malformed control infants were selected using birth certificates or hospital records. Maternal solvent exposure was estimated by industrial hygienist review of self-reported occupational histories in combination with a literature-derived exposure database. Odds ratios (OR) and 95% confidence intervals (CI) for the association between solvent class and each birth defect group and component phenotype were estimated using multivariable logistic regression, adjusting for maternal age, race/ethnicity, education, pre-pregnancy body mass index, folic acid supplement use and smoking.
The prevalence of exposure to any solvent among mothers of NTD cases (n=511), OFC cases (n=1163) and controls (n=2977) was 13.1%, 9.6% and 8.2%, respectively. Exposure to chlorinated solvents was associated with increased odds of NTDs (OR=1.96; CI=1.34, 2.87), especially spina bifida (OR=2.26; CI=1.44, 3.53). No solvent class was strongly associated with OFCs in these data.
Our findings suggest that maternal occupational exposure to chlorinated solvents during early pregnancy is positively associated with the prevalence of NTDs in offspring.
PMCID: PMC3719396  PMID: 22447643
congenital abnormalities; occupational exposure; solvents
13.  Airline Pilot Cosmic Radiation and Circadian Disruption Exposure Assessment from Logbooks and Company Records 
Annals of Occupational Hygiene  2011;55(5):465-475.
Objectives: US commercial airline pilots, like all flight crew, are at increased risk for specific cancers, but the relation of these outcomes to specific air cabin exposures is unclear. Flight time or block (airborne plus taxi) time often substitutes for assessment of exposure to cosmic radiation. Our objectives were to develop methods to estimate exposures to cosmic radiation and circadian disruption for a study of chromosome aberrations in pilots and to describe workplace exposures for these pilots.
Methods: Exposures were estimated for cosmic ionizing radiation and circadian disruption between August 1963 and March 2003 for 83 male pilots from a major US airline. Estimates were based on 523 387 individual flight segments in company records and pilot logbooks as well as summary records of hours flown from other sources. Exposure was estimated by calculation or imputation for all but 0.02% of the individual flight segments’ block time. Exposures were estimated from questionnaire data for a comparison group of 51 male university faculty.
Results: Pilots flew a median of 7126 flight segments and 14 959 block hours for 27.8 years. In the final study year, a hypothetical pilot incurred an estimated median effective dose of 1.92 mSv (absorbed dose, 0.85 mGy) from cosmic radiation and crossed 362 time zones. This study pilot was possibly exposed to a moderate or large solar particle event a median of 6 times or once every 3.7 years of work. Work at the study airline and military flying were the two highest sources of pilot exposure for all metrics. An index of work during the standard sleep interval (SSI travel) also suggested potential chronic sleep disturbance in some pilots. For study airline flights, median segment radiation doses, time zones crossed, and SSI travel increased markedly from the 1990s to 2003 (Ptrend < 0.0001). Dose metrics were moderately correlated with records-based duration metrics (Spearman’s r = 0.61–0.69).
Conclusions: The methods developed provided an exposure profile of this group of US airline pilots, many of whom have been exposed to increasing cosmic radiation and circadian disruption from the 1990s through 2003. This assessment is likely to decrease exposure misclassification in health studies.
PMCID: PMC3113148  PMID: 21610083
circadian disruption; cosmic radiation; exposure assessment; flight crew; pilots
14.  Maternal Occupational Exposure to Polycyclic Aromatic Hydrocarbons: Effects on Gastroschisis among Offspring in the National Birth Defects Prevention Study 
Environmental Health Perspectives  2012;120(6):910-915.
Background: Exposure to polycyclic aromatic hydrocarbons (PAHs) occurs in many occupational settings. There is evidence in animal models that maternal exposure to PAHs during pregnancy is associated with gastroschisis in offspring; however, to our knowledge, no human studies examining this association have been conducted.
Objective: Our goal was to conduct a case–control study assessing the association between estimated maternal occupational exposure to PAHs and gastroschisis in offspring.
Methods: Data from gastroschisis cases and control infants were obtained from the population-based National Birth Defects Prevention Study for the period 1997–2002. Exposure to PAHs was assigned by industrial hygienist consensus, based on self-reported maternal occupational histories from 1 month before conception through the third month of pregnancy. Logistic regression was used to determine the association between estimated occupational PAH exposure and gastroschisis among children whose mothers were employed for at least 1 month during the month before conception through the third month of pregnancy.
Results: The prevalence of estimated occupational PAH exposure was 9.0% in case mothers (27 of 299) and 3.6% in control mothers (107 of 2,993). Logistic regression analyses indicated a significant association between occupational PAHs and gastroschisis among mothers ≥ 20 years of age [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.27, 5.04] after adjusting for maternal body mass index, education, gestational diabetes, and smoking. This association was not seen in mothers < 20 years (OR = 1.14; 95% CI: 0.55, 2.33), which is notable because although young maternal age is the strongest known risk factor for gastroschisis, most cases are born to mothers ≥ 20 years.
Conclusion: Our findings indicate an association between occupational exposure to PAHs among mothers who are ≥ 20 years and gastroschisis. These results contribute to a body of evidence that PAHs may be teratogenic.
PMCID: PMC3385431  PMID: 22330681
birth defects; gastroschisis; maternal exposure; occupation; PAHs
15.  Statistical modeling of occupational chlorinated solvent exposures for case–control studies using a literature-based database 
Annals of Occupational Hygiene  2010;54(4):459-472.
Objectives: Occupational exposure assessment for population-based case–control studies is challenging due to the wide variety of industries and occupations encountered by study participants. We developed and evaluated statistical models to estimate the intensity of exposure to three chlorinated solvents—methylene chloride, 1,1,1-trichloroethane, and trichloroethylene—using a database of air measurement data and associated exposure determinants.
Methods: A measurement database was developed after an extensive review of the published industrial hygiene literature. The database of nearly 3000 measurements or summary measurements included sample size, measurement characteristics (year, duration, and type), and several potential exposure determinants associated with the measurements: mechanism of release (e.g. evaporation), process condition, temperature, usage rate, type of ventilation, location, presence of a confined space, and proximity to the source. The natural log-transformed measurement levels in the exposure database were modeled as a function of the measurement characteristics and exposure determinants using maximum likelihood methods. Assuming a single lognormal distribution of the measurements, an arithmetic mean exposure intensity level was estimated for each unique combination of exposure determinants and decade.
Results: The proportions of variability in the measurement data explained by the modeled measurement characteristics and exposure determinants were 36, 38, and 54% for methylene chloride, 1,1,1-trichloroethane, and trichloroethylene, respectively. Model parameter estimates for the exposure determinants were in the anticipated direction. Exposure intensity estimates were plausible and exhibited internal consistency, but the ability to evaluate validity was limited.
Conclusions: These prediction models can be used to estimate chlorinated solvent exposure intensity for jobs reported by population-based case–control study participants that have sufficiently detailed information regarding the exposure determinants.
PMCID: PMC2913720  PMID: 20418277
case–control study; exposure assessment; exposure determinants; occupational exposure
16.  Maternal exposure to polychlorinated biphenyls and the secondary sex ratio: an occupational cohort study 
Environmental Health  2011;10:20.
Though commercial production of polychlorinated biphenyls was banned in the United States in 1977, exposure continues due to their environmental persistence. Several studies have examined the association between environmental polychlorinated biphenyl exposure and modulations of the secondary sex ratio, with conflicting results.
Our objective was to evaluate the association between maternal preconceptional occupational polychlorinated biphenyl exposure and the secondary sex ratio.
We examined primipara singleton births of 2595 women, who worked in three capacitor plants at least one year during the period polychlorinated biphenyls were used. Cumulative estimated maternal occupational polychlorinated biphenyl exposure at the time of the infant's conception was calculated from plant-specific job-exposure matrices. A logistic regression analysis was used to evaluate the association between maternal polychlorinated biphenyl exposure and male sex at birth (yes/no).
Maternal body mass index at age 20, smoking status, and race did not vary between those occupationally exposed and those unexposed before the child's conception. Polychlorinated biphenyl-exposed mothers were, however, more likely to have used oral contraceptives and to have been older at the birth of their first child than non-occupationally exposed women. Among 1506 infants liveborn to polychlorinated biphenyl-exposed primiparous women, 49.8% were male; compared to 49.9% among those not exposed (n = 1089). Multivariate analyses controlling for mother's age and year of birth found no significant association between the odds of a male birth and mother's cumulative estimated polychlorinated biphenyl exposure to time of conception.
Based on these data, we find no evidence of altered sex ratio among children born to primiparous polychlorinated biphenyl-exposed female workers.
PMCID: PMC3070618  PMID: 21418576
17.  Occupational Exposure to Polychlorinated Biphenyls and Risk of Breast Cancer 
Environmental Health Perspectives  2008;117(2):276-282.
Despite the endocrine system activity exhibited by polychlorinated biphenyls (PCBs), recent studies have shown little association between PCB exposure and breast cancer mortality.
To further evaluate the relation between PCB exposure and breast cancer risk, we studied incidence, a more sensitive end point than mortality, in an occupational cohort.
We followed 5,752 women employed for at least 1 year in one of three capacitor manufacturing facilities, identifying cases from questionnaires, cancer registries, and death certificates through 1998. We collected lifestyle and reproductive information via questionnaire from participants or next of kin and used semiquantitative job-exposure matrices for inhalation and dermal exposures combined. We generated standardized incidence ratios (SIRs) and standardized rate ratios and used Cox proportional hazards regression models to evaluate potential confounders and effect modifiers.
Overall, the breast cancer SIR was 0.81 (95% confidence interval, 0.72–0.92; n = 257), and regression modeling showed little effect of employment duration or cumulative exposure. However, for the 362 women of questionnaire-identified races other than white, we observed positive, statistically significant associations with employment duration and cumulative exposure; only smoking, birth cohort, and self- or proxy questionnaire completion had statistically significant explanatory power when added to models with exposure metrics.
We found no overall elevation in breast cancer risk after occupational exposure to PCBs. However, the exposure-related risk elevations seen among nonwhite workers, although of limited interpretability given the small number of cases, warrant further investigation, because the usual reproductive risk factors accounted for little of the increased risk.
PMCID: PMC2649231  PMID: 19270799
breast cancer; incidence; occupational epidemiology; polychlorinated biphenyls
18.  Mortality and Exposure Response among 14,458 Electrical Capacitor Manufacturing Workers Exposed to Polychlorinated Biphenyls (PCBs) 
Environmental Health Perspectives  2006;114(10):1508-1514.
We expanded an existing cohort of workers (n = 2,588) considered highly exposed to polychlorinated biphenyls (PCBs) at two capacitor manufacturing plants to include all workers with at least 90 days of potential PCB exposure during 1939–1977 (n = 14,458). Causes of death of a priori interest included liver and rectal cancers, previously reported for the original cohort, and non-Hodgkin lymphoma (NHL), melanoma, and breast, brain, intestine, stomach, and prostate cancers, based on other studies.
We ascertained vital status of the workers through 1998, and cumulative PCB exposure was estimated using a new job exposure matrix. Analyses employed standardized mortality ratios (SMRs; U.S., state, and county referents) and Poisson regression modeling.
Mortality from NHL, melanoma, and rectal, breast, and brain cancers were neither in excess nor associated with cumulative exposure. Mortality was not elevated for liver cancer [21 deaths; SMR 0.89; 95% confidence interval (CI), 0.55–1.36], but increased with cumulative exposure (trend p-value = 0.071). Among men, stomach cancer mortality was elevated (24 deaths; SMR 1.53; 95% CI, 0.98–2.28) and increased with cumulative exposure (trend p-value = 0.039). Among women, intestinal cancer mortality was elevated (67 deaths; SMR 1.31; 95% CI, 1.02–1.66), especially in higher cumulative exposure categories, but without a clear trend. Prostate cancer mortality, which was not elevated (34 deaths; SMR 1.04; 95% CI, 0.72–1.45), increased with cumulative exposure (trend p-value = 0.0001).
This study corroborates previous studies showing increased liver cancer mortality, but we cannot clearly associate rectal, stomach, and intestinal cancers with PCB exposure. This is the first PCB cohort showing a strong exposure–response relationship for prostate cancer mortality.
PMCID: PMC1626402  PMID: 17035134
cancer; electrical capacitor manufacturing; liver cancer; mortality; occupational exposure; PCBs; polychlorinated biphenyls; prostate cancer
19.  Update: cohort mortality study of workers highly exposed to polychlorinated biphenyls (PCBs) during the manufacture of electrical capacitors, 1940-1998 
Environmental Health  2006;5:13.
The National Institute for Occupational Safety and Health previously reported mortality for a cohort of workers considered highly exposed to polychlorinated biphenyls (PCBs) between 1939 and 1977 at two electrical capacitor manufacturing plants. The current study updated vital status, examined liver and rectal cancer mortality previously reported in excess in this cohort and evaluated mortality from non-Hodgkin's lymphoma (NHL) and cancers of the stomach, intestine, breast, prostate, skin (melanoma) and brain reported to be in excess in other cohort and case-control studies of PCB-exposed persons.
Mortality was updated through 1998 for 2572 workers. Age-, gender-, race- and calendar year-adjusted standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using U.S., state and county referent rates. SMRs using U.S. referent rates are reported. Duration of employment was used as a surrogate for exposure.
Consistent with the previous follow-up, mortality from biliary passage, liver and gall bladder cancer was significantly elevated (11 deaths, SMR 2.11, CI 1.05 – 3.77), but mortality from rectal cancer was not (6 deaths, SMR 1.47, CI 0.54 – 3.21). Among women, mortality from intestinal cancer (24 deaths, SMR 1.89, CI 1.21 – 2.82) and from "other diseases of the nervous system and sense organs", which include Parkinson's disease and amyotrophic lateral sclerosis, (15 deaths, SMR 2.07, CI 1.16 – 3.42) were elevated. There were four ALS deaths, all women (SMR 4.35, CI 1.19–11.14). Mortality was elevated for myeloma (7 deaths, SMR 2.11, CI 0.84 – 4.34), particularly among workers employed 10 years or more (5 deaths, SMR 2.80, CI 0.91 – 6.54). No linear associations between mortality and duration of employment were observed for the cancers of interest.
This update found that the earlier reported excess in this cohort for biliary, liver and gall bladder cancer persisted with longer follow-up. Excess mortality for intestinal cancer among women was elevated across categories of duration of employment; myeloma mortality was highest among those working 10 years or more. The small numbers of deaths from liver and intestinal cancers, myeloma and nervous system diseases coupled with the lack of an exposure-response relationship with duration of employment preclude drawing definitive conclusions regarding PCB exposure and these causes of death.
PMCID: PMC1524943  PMID: 16716225
20.  Mortality among Workers Exposed to Polychlorinated Biphenyls (PCBs) in an Electrical Capacitor Manufacturing Plant in Indiana: An Update 
An Indiana capacitor-manufacturing cohort (n = 3,569) was exposed to polychlorinated biphenyls (PCBs) from 1957 to 1977. The original study of mortality through 1984 found excess melanoma and brain cancer; other studies of PCB-exposed individuals have found excess non-Hodgkin lymphoma and rectal, liver, biliary tract, and gallbladder cancer. Mortality was updated through 1998. Analyses have included standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) using rates for Indiana and the United States, standardized rate ratios (SRRs), and Poisson regression rate ratios (RRs). Estimated cumulative exposure calculations used a new job–exposure matrix. Mortality overall was reduced (547 deaths; SMR, 0.81; 95% CI, 0.7–0.9). Non-Hodgkin lymphoma mortality was elevated (9 deaths; SMR, 1.23; 95% CI, 0.6–2.3). Melanoma remained in excess (9 deaths; SMR, 2.43; 95% CI, 1.1–4.6), especially in the lowest tertile of estimated cumulative exposure (5 deaths; SMR, 3.72; 95% CI, 1.2–8.7). Seven of the 12 brain cancer deaths (SMR, 1.91; 95% CI, 1.0–3.3) occurred after the original study. Brain cancer mortality increased with exposure (in the highest tertile, 5 deaths; SMR, 2.71; 95% CI, 0.9–6.3); the SRR dose–response trend was significant (p = 0.016). Among those working ≥90 days, both melanoma (8 deaths; SMR, 2.66; 95% CI, 1.1–5.2) and brain cancer (11 deaths; SMR, 2.12; 95% CI, 1.1–3.8) were elevated, especially for women: melanoma, 3 deaths (SMR, 5.99; 95% CI, 1.2–17.5); brain cancer, 3 deaths (SMR, 2.87; 95% CI, 0.6–8.4). These findings of excess melanoma and brain cancer mortality confirm results of the original study. Melanoma mortality was not associated with estimated cumulative exposure. Brain cancer mortality did not demonstrate a clear dose–response relationship with estimated cumulative exposure.
PMCID: PMC1332650  PMID: 16393652
cancer; cohort study; exposure assessment; occupational exposure; polychlorinated biphenyls
21.  Gliomas and Farm Pesticide Exposure in Women: The Upper Midwest Health Study 
Environmental Health Perspectives  2005;113(5):546-551.
An excess incidence of brain cancer in male farmers has been noted in several studies, but few studies have focused on women. The National Institute for Occupational Safety and Health Upper Midwest Health Study evaluated effects of rural exposures for 341 female glioma cases and 528 controls, all adult (18–80 years of age) nonmetropolitan residents of Iowa, Michigan, Minnesota, and Wisconsin. On average, controls lived longer on farms than did cases. After adjusting for age, age group, education, and farm residence, no association with glioma was observed for exposure to arsenicals, benzoic acids, carbamates, chloroacetanilides, dinitroanilines, inorganics, organochlorines, organophosphates, phenoxys, triazines, or urea-based or estrogenic pesticides. An increased risk of glioma was observed for carbamate herbicides but was not statistically significant (odds ratio = 3.0; 95% confidence interval, 0.9–9.5). No association was observed between glioma and exposure to 12 widely used specific pesticides, after adjustment for age, age group, education, and any other pesticide exposure. These results were not affected after exclusion of proxy respondents (43% of cases, 2% of controls). Women were less likely than men to have applied pesticides, but more likely to have laundered pesticide-contaminated clothes. Storing pesticides in the house was associated with a statistically non-significant increased risk. Results show that exposure to pesticides was not associated with an increased risk of intracranial gliomas in women. Other farm-related factors could be etiologic factors and will be discussed in future reports.
PMCID: PMC1257545  PMID: 15866761
brain cancer; case—control; farmers; glioma; Midwest; pesticides; women

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