Breast cancer among women in Michigan following exposure to brominated flame retardants.

In this updated follow-up, we investigated the breast cancer experience among women in Michigan exposed to brominated flame retardants, some 30 years following exposure. Michigan residents were enrolled in a study cohort after exposure to polybrominated biphenyls (PBBs) through the consumption of contaminated food products. PBB concentrations were measured in serum at the time of enrolment. Cancer experience was determined by linkage to the Michigan Cancer Registry. We conducted a nested case-control study that included 51 women diagnosed with breast cancer during 1974-2004 and 202 age-matched controls. While the data suggest an increase in breast cancer risk with higher PBB exposure, this did not reach statistical significance. The OR of having breast cancer among women with PBB concentrations ≥10 ng/mL compared to women with PBB concentrations at or below the limit of detection of 1 ng/mL was 2.60, 95% CI 0.93 to 7.27, (p=0.07), when adjusted for age and family history of cancer in a first-degree female relative. It remains important to examine exposure to brominated chemicals and possible health effects, and to continue following the cancer experience of participants in this study.

Neonatal withdrawal syndrome, Michigan, 2000-2009.

BACKGROUND: Neonatal withdrawal syndrome, which is associated most frequently with opioid use in pregnancy, is an emerging public health concern, with recent studies documenting an increase in the rate of U.S. infants diagnosed. PURPOSE: This study examined neonatal withdrawal syndrome diagnosis among Michigan infants from 2000 to 2009 and hospital length of stay (LOS) between infants with and without the syndrome for a subset of years (2006-2009). METHODS: Michigan live birth records from 2000 to 2009 were linked with hospital discharge data to identify infants with neonatal withdrawal syndrome. Linked data were restricted to infants born between 2006 and 2009 to examine the difference in hospital LOS between infants with and without the syndrome. Multivariable regression models were constructed to examine the adjusted impact of syndrome diagnosis on infant LOS and fit using negative binomial distribution. Data were analyzed from July 2011 to February 2012. RESULTS: From 2000 to 2009, the overall birth rate of infants with neonatal withdrawal syndrome increased from 41.2 to 289.0 per 100,000 live births (p<0.0001). Among infants born from 2006 to 2009, the average hospital LOS for those with the syndrome was between 1.36 (95% CI=1.24, 1.49) and 5.75 (95% CI=5.41, 6.10) times longer than for infants without it. CONCLUSIONS: Diagnosis of neonatal withdrawal syndrome increased significantly in Michigan with infants who had the syndrome requiring a significantly longer LOS compared to those without it.

Dietary exposure to brominated flame retardants and abnormal Pap test results.

OBJECTIVE: This study examined a possible association of dietary exposure to polybrominated biphenyls (PBBs), a brominated flame retardant, and self-reported abnormal Pap test results and cervical dysplasia as a precursor to cervical cancer. METHODS: Women in Michigan who ingested contaminated poultry, beef, and dairy products in the early 1970s were enrolled in a population-based cohort study in Michigan. Serum PBB and serum polychlorinated biphenyl (PCB) concentrations were measured. Reproductive history and health information, including Pap test results, were self-reported by participants. RESULTS: Of the women, 23% (223 of 956) reported an abnormal Pap test. In unadjusted analyses, self-reporting an abnormal Pap test was associated with younger age, current smoking (hazard ratio [HR] 1.61, 95% confidence interval [CI] 1.19-2.17), and longer duration of lifetime use of oral contraceptives (≥10 years; HR 1.92, 95% CI 1.21-3.06). When adjusting for PCB exposure, age at the interview, and smoking history, there was a slightly elevated risk of self-reporting an abnormal Pap test among the highly exposed women compared to women with nondetectable PBB concentrations (PBB≥13 µg/L, HR 1.23, 95% CI 0.74-2.06); however, the CI was imprecise. When breastfeeding duration after the initial PBB measurement was taken into account, there was a reduced risk of self-reporting an abnormal Pap test among the highly exposed women who breastfed for ≥12 months (HR 0.41, 95% CI 0.06-3.03; referent group: women with nondetectable PBB concentrations who did not breastfeed). CONCLUSIONS: It remains important to evaluate the potential reproductive health consequences of this class of chemicals as well as other potential predictors of abnormal Pap tests.

Incidence of thyroid disease following exposure to polybrominated biphenyls and polychlorinated biphenyls, Michigan, 1974-2006.

Thyroid hormones, which influence body metabolism and development, could be affected by persistent organic pollutants. We sought to examine the relationship between polybrominated biphenyls (PBBs) and polychlorinated biphenyls (PCBs) and thyroid disease. We employed incidence density sampling to perform a nested case control analysis of the Michigan Long-Term PBB Cohort. Cohort members (n=3333) were exposed to PBBs through contaminated cattle feed in 1973-1974 and to PCBs through daily life. Those with detectable serum PBB and PCB concentrations at enrollment were categorized into tertiles of PBB and PCB exposure. Case-patients were cohort members answering "Yes" to "Has a healthcare provider ever told you that you had a thyroid problem?" during follow-up interviews; control-patients were cohort members answering "No". We used odds ratios (OR) with 95% confidence intervals (CI) to compare odds of thyroid disease by PBB and PCB exposure and by various risk factors. Total cumulative thyroid disease incidence after 33 years was 13.9% among women and 2.6% among men. After adjusting for body mass index, we found no statistically significant differences in odds of any type of thyroid disease among women or men with elevated PBB or PCB exposure. Compared to control-patients, women with thyroid disease had increased odds of being overweight/obese (OR=2.82, 95% CI: 1.94-4.11) and developing infertility (OR=1.71, 95% CI: 1.08-2.69), diabetes (OR=1.61, 95% CI: 1.04-2.51), or arthritis (OR=1.71, 95% CI: 1.18-2.50) during follow-up. Additional research should explore potential associations between PBBs/PCBs and thyroid disease among children exposed in utero.

Maternal exposure to a brominated flame retardant and genitourinary conditions in male offspring.

BACKGROUND: The upward trend in industrial nations in the incidence of male genitourinary (GU) conditions may be attributed to increased exposure to endocrine disruptors. Polybrominated biphenyl (PBB), a brominated flame retardant, is one such suspected endocrine disruptor. OBJECTIVE: We investigated the relationship between maternal serum levels of PBBs and GU conditions among male offspring exposed in utero. METHODS: In this cohort study of sons born to women accidentally exposed to PBBs during 1973-1974, we examined self-reported data on GU conditions among male offspring in relation to maternal serum PBB levels. We used generalized estimating equations to calculate odds ratios (ORs), controlling for gestational age at birth. RESULTS: Of 464 sons, 33 reported any GU condition (13 hernias, 10 hydroceles, 9 cryptorchidism, 5 hypospadias, and 1 varicocele). Four reported both hernia and hydrocele, and one both hernia and cryptorchidism. After adjustment for gestational age at birth, sons of highly exposed women (> 5 ppb) were twice as likely to report any GU condition compared with sons of the least exposed women [< or =1 ppb; OR = 2.0; 95% confidence interval (CI), 0.8-5.1]. This risk was increased when we excluded sons born after the exposure but before the mother's serum PBB measurement (OR = 3.1; 95% CI, 1.0-9.1). We found evidence of a 3-fold increase in reported hernia or hydrocele among sons with higher PBB exposure (test of trend p-value = 0.04). Neither hypospadias nor cryptorchidism was individually associated with PBB exposure. CONCLUSIONS: Although cryptorchidism and hypospadias were not associated with in utero PBB exposure, this study suggests that other GU conditions may be associated with exposure to endocrine-disrupting chemicals during development.

A cohort study of the association between secondary sex ratio and parental exposure to polybrominated biphenyl (PBB) and polychlorinated biphenyl (PCB).

BACKGROUND: Polybrominated biphenyl (PBB), a brominated flame retardant, was accidently mixed into animal feed in Michigan (1973-1974) resulting in human exposure through consumption of contaminated meat, milk and eggs. Beginning in 1976 individuals who consumed contaminated products were enrolled in the Michigan Long-Term PBB Study. This cohort presents a unique opportunity to study the association between parental exposures to PBB and offspring sex ratio. METHODS: We identified offspring of female PBB cohort participants (born 1975-1988) and obtained electronic birth records for those born in the state of Michigan. We linked this information to parental serum PBB and PCB concentrations collected at enrollment into the cohort. We modeled the odds of a male birth with generalized estimating equations accounting for the non-independence of siblings born to the same parents. We explored potential confounders: parental age and education at offspring's birth, parental body mass index at cohort enrollment, birth order, gestational age and year of offspring's birth. RESULTS: The overall proportion of male offspring among 865 live births to cohort mothers was 0.542. This was higher than the national male proportion of 0.514 (binomial test: p = 0.10). When both parents were in the cohort (n = 300), we found increased odds of a male birth with combined parents' enrollment PBB exposure > or = the median concentrations (3 microg/L for mothers; 6 microg/L for fathers) compared to combined parents' PBB exposure < the median concentrations (AOR = 1.43, 95% CI: 0.89-2.29), although this did not reach statistical significance. In addition, there was a suggestion of increased odds of a male birth for combined parents' enrollment PCB exposure > or = the median concentrations (6 microg/L for mothers; 8 microg/L for fathers) compared to combined parents' enrollment PCB exposure < the median concentrations (AOR = 1.53, 95% CI: 0.93-2.52). CONCLUSION: This study adds to the body of literature on secondary sex ratio and exposure to environmental contaminants. In this population, combined parental exposure to PBBs or PCBs increased the odds of a male birth. Further research is needed to corroborate these findings and shed light on the biological mechanisms by which these types of chemicals may influence the secondary sex ratio.

Assessing inter-generational transfer of a brominated flame retardant.

Studies have shown that the lipophilic nature of polybrominated biphenyl (PBB) causes it to preferentially accumulate in breast milk posing a potential hazard for suckling infants. The purpose of this study was to examine the inter-generational transfer of PBB from mother to child and whether this association was modified by maternal breast-feeding patterns. One hundred and forty-five mother-child pairs that were participants of the Michigan Long-Term PBB Study were included in this analysis. Mothers were exposed to PBB via contaminated food between 1973 and 1974 and children were exposed in utero and for some, through breast-feeding. Seventy-three percent of children had a non-detectable serum PBB concentration (limit of detection (LOD) = 1 microg L(-1)). Mothers' serum PBB concentration at enrollment ranged from or =8 microg L(-1), breast-feeding > or =5.5 months, maternal age at child's birth > or =28 years, and being born during the PBB exposure period. Among mothers with a detectable serum PBB concentration, those who breast-fed > or =5.5 months were 6 times more likely to have a child with a detectable serum PBB concentration, compared to a non-breast-fed child (95% C.I., 2.0-19.6).

In utero exposure to a brominated flame retardant and male growth and development.

Whether environmental exposures alter the timing of puberty is the subject of increasing interest as pubertal age may have consequences for long term health. This study examines the association between exposure to a brominated flame retardant, polybrominated biphenyl (PBB), and puberty and growth. The population consists of sons born to women accidentally exposed to PBBs during 1973-74. Sons 5 to 17 years reported Tanner Stages and answered questions regarding current growth in a mailed questionnaire. Sons 18 to 30 years of age participated in a telephone interview in which they reported retrospective measures of development. Among sons 5-17 years, those with highest exposure (>3 ppb) were less likely to report advanced Tanner stage genital development (OR=0.4, 95% CI: 0.2-0.9) and were less likely to report advanced pubic hair development (OR=0.5; 95% CI: 0.2-1.0), after adjusting for current age, compared to those with lowest exposure (<= 1 ppb). No differences were seen in growth among sons 5-17. However, among sons 18-30 years, those with higher exposure were more likely to weigh less and have lower BMI as adults (test of trend p=0.01 and 0.04, respectively). They were less likely to recall being tall (OR=0.5; 95% CI 0.2-0.9) or heavy (OR=0.6; 95% CI 0.3-1.1) compared to their peers at age 11 years. These results suggest that sons exposed to PBBs in utero may be more likely to have delayed puberty. Further research is needed to corroborate these findings among structurally related compounds and shed light on the biological mechanisms that may be disrupted during puberty and development.

A decay model for assessing polybrominated biphenyl exposure among women in the Michigan Long-Term PBB Study.

The Michigan Long-Term PBB Study was established following exposure to polybrominated biphenyls (PBBs) in the early 1970s. Serum samples from cohort members were analyzed for PBB during 1976-1993. More than 20 years following this industrial incident, some participants still had measurable serum PBB concentration levels. Thus, there is continuing interest in understanding the elimination of PBB from the body. In the present study, we estimated serum PBB decay and investigated the effects of covariates on serum PBB decay rates among 406 female cohort members. We developed a decay model using a general linear mixed model, which attributes unique intercept and slope estimates for each individual while borrowing information across individuals for predicting these quantities. Age at exposure and body mass index (BMI) at the initial measurement were time-independent covariates. Time since exposure, smoking history, pregnancy status, and breast-feeding status were time-dependent covariates. Higher BMI was associated with a slower decay rate; smokers had a faster decay rate than nonsmokers; and increasing age at exposure was marginally associated with a slower decay rate. Our results suggest a faster serum PBB decay rate for women who breast-fed during the interval between serum PBB measurements. To evaluate the predictive performance of our modeling approach, we compared the results from this model with those from a previously developed ordinary least squares (OLS) two-stage decay model. The mixed-effects decay model predicted the observed serum PBB concentration levels significantly better than the OLS two-stage decay model (mixed-effects model, r=0.93; OLS two-stage model, r=0.86; P<0.0001).

Maternal exposure to polybrominated and polychlorinated biphenyls: infant birth weight and gestational age.

Understanding the influence of maternal exposures on gestational age and birth weight is essential given that pre-term and/or low birth weight infants are at risk for increased mortality and morbidity. We performed a retrospective analysis of a cohort exposed to polybrominated biphenyls (PBB) through accidental contamination of cattle feed and polychlorinated biphenyls (PCB) through residual contamination in the geographic region. Our study population consisted of 444 mothers and their 899 infants born between 1975 and 1997. Using restricted maximum likelihood estimation, no significant association was found between estimated maternal serum PBB at conception or enrollment PCB levels and gestational age or infant birth weight in unadjusted models or in models that adjusted for maternal age, smoking, parity, infant gender, and decade of birth. For enrollment maternal serum PBB, no association was observed for gestational age. However, a negative association with high levels of enrollment maternal serum PBB and birth weight was suggested. We also examined the birth weight and gestational age among offspring of women with the highest (10%) PBB or PCB exposure, and observed no significant association. Because brominated compounds are currently used in consumer products and therefore, are increasingly prevalent in the environment, additional research is needed to better understand the potential relationship between in utero exposure to brominated compounds and adverse health outcomes.

Arsenic in drinking water and cerebrovascular disease, diabetes mellitus, and kidney disease in Michigan: a standardized mortality ratio analysis.

BACKGROUND: Exposure to arsenic concentrations in drinking water in excess of 300 microg/L is associated with diseases of the circulatory and respiratory system, several types of cancer, and diabetes; however, little is known about the health consequences of exposure to low-to-moderate levels of arsenic (10-100 microg/L). METHODS: A standardized mortality ratio (SMR) analysis was conducted in a contiguous six county study area of southeastern Michigan to investigate the relationship between moderate arsenic levels and twenty-three selected disease outcomes. Disease outcomes included several types of cancer, diseases of the circulatory and respiratory system, diabetes mellitus, and kidney and liver diseases. Arsenic data were compiled from 9251 well water samples tested by the Michigan Department of Environmental Quality from 1983 through 2002. Michigan Resident Death Files data were amassed for 1979 through 1997 and sex-specific SMR analyses were conducted with indirect adjustment for age and race; 99% confidence intervals (CI) were reported. RESULTS: The six county study area had a population-weighted mean arsenic concentration of 11.00 microg/L and a population-weighted median of 7.58 microg/L. SMR analyses were conducted for the entire six county study area, for only Genesee County (the most populous and urban county), and for the five counties besides Genesee. Concordance of results across analyses is used to interpret the findings. Elevated mortality rates were observed for both males (M) and females (F) for all diseases of the circulatory system (M SMR, 1.11; CI, 1.09-1.13; F SMR, 1.15; CI, 1.13,-1.17), cerebrovascular diseases (M SMR, 1.19; CI, 1.14-1.25; F SMR, 1.19; CI, 1.15-1.23), diabetes mellitus (M SMR, 1.28; CI, 1.18-1.37; F SMR, 1.27; CI, 1.19-1.35), and kidney diseases (M SMR, 1.28; CI, 1.15-1.42; F SMR, 1.38; CI, 1.25-1.52). CONCLUSION: This is some of the first evidence to suggest that exposure to low-to-moderate levels of arsenic in drinking water may be associated with several of the leading causes of mortality, although further epidemiologic studies are required to confirm the results suggested by this ecologic SMR analysis.

Menstrual function among women exposed to polybrominated biphenyls: a follow-up prevalence study.

BACKGROUND: Alteration in menstrual cycle function is suggested among rhesus monkeys and humans exposed to polybrominated biphenyls (PBBs) and structurally similar polychlorinated biphenyls (PCBs). The feedback system for menstrual cycle function potentially allows multiple pathways for disruption directly through the hypothalamic-pituitary-ovarian axis and indirectly through alternative neuroendocrine axes. METHODS: The Michigan Female Health Study was conducted during 1997-1998 among women in a cohort exposed to PBBs in 1973. This study included 337 women with self-reported menstrual cycles of 20-35 days (age range: 24-56 years). Current PBB levels were estimated by exponential decay modeling of serum PBB levels collected from 1976-1987 during enrollment in the Michigan PBB cohort. Linear regression models for menstrual cycle length and the logarithm of bleed length used estimated current PBB exposure or enrollment PBB exposure categorized in tertiles, and for the upper decile. All models were adjusted for serum PCB levels, age, body mass index, history of at least 10% weight loss in the past year, physical activity, smoking, education, and household income. RESULTS: Higher levels of physical activity were associated with shorter bleed length, and increasing age was associated with shorter cycle length. Although no overall association was found between PBB exposure and menstrual cycle characteristics, a significant interaction between PBB exposures with past year weight loss was found. Longer bleed length and shorter cycle length were associated with higher PBB exposure among women with past year weight loss. CONCLUSION: This study suggests that PBB exposure may impact ovarian function as indicated by menstrual cycle length and bleed length. However, these associations were found among the small number of women with recent weight loss suggesting either a chance finding or that mobilization of PBBs from lipid stores may be important. These results should be replicated with larger numbers of women exposed to similar lipophilic compounds.

Proportionate mortality of crop and livestock farmers in the United States, 1984-1993.

BACKGROUND: Livestock farmers are more likely to be exposed to a variety of different farming hazards than crop farmers. An analysis of occupation and industry-coded U.S. death certificate data from 26 states for the years 1984-1993 was conducted to evaluate mortality patterns among crop and livestock farmers. METHODS: Cause-specific proportionate mortality ratios (PMRs) were calculated using a National Institute for Occupational Safety and Health (NIOSH) computer program designed to calculate sex and race specific PMRs for occupations and industries in population-based data. RESULTS: Among white male (WM) livestock farmers, there was a significantly higher mortality from cancer of the pancreas, prostate and brain, non-Hodgkin's lymphoma (NHL), multiple myeloma, acute and chronic lymphoid leukemia, and Parkinson's disease. WM crop farmers showed significantly higher mortality risk for cancer of the lip, skin, multiple myeloma, and chronic lymphoid leukemia. CONCLUSIONS: These disease trends suggested that livestock farmers might be exposed to more carcinogens or agricultural chemicals than crop farmers.