Kyle Steenland

Cancer mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

BACKGROUND In both animal and epidemiologic studies, exposure to dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin, or TCDD) has been associated with an increased risk of cancer. METHODS We conducted a retrospective cohort study of mortality among the 5172 workers at 12 plants in the United States that produced chemicals contaminated with TCDD. Occupational exposure was documented by reviewing job descriptions and by measuring TCDD in serum from a sample of 253 workers. Causes of death were taken from death certificates. RESULTS Mortality from several cancers previously associated with TCDD (stomach, liver, and nasal cancers, Hodgkins disease, and non-Hodgkins lymphoma) was not significantly elevated in this cohort. Mortality from soft-tissue sarcoma was increased, but not significantly (4 deaths; standardized mortality ratio [SMR], 338; 95 percent confidence interval, 92 to 865). In the subcohort of 1520 workers with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency, however, mortality was significantly increased for soft-tissue sarcoma (3 deaths; SMR, 922; 95 percent confidence interval, 190 to 2695) and for cancers of the respiratory system (SMR, 142; 95 percent confidence interval, 103 to 192). Mortality from all cancers combined was slightly but significantly elevated in the overall cohort (SMR, 115; 95 percent confidence interval, 102 to 130) and was higher in the subcohort with greater than or equal to 1 year of exposure and greater than or equal to 20 years of latency (SMR, 146; 95 percent confidence interval, 121 to 176). CONCLUSIONS This study of mortality among workers with occupational exposure to TCDD does not confirm the high relative risks reported for many cancers in previous studies. Conclusions about an increase in the risk of soft-tissue sarcoma are limited by small numbers and misclassification on death certificates. Excess mortality from all cancers combined, cancers of the respiratory tract, and soft-tissue sarcoma may result from exposure to TCDD, although we cannot exclude the possible contribution of factors such as smoking and occupational exposure to other chemicals.

Epidemiologic evidence on the health effects of perfluorooctanoic acid (PFOA).

Objective and sources We reviewed the epidemiologic literature for PFOA. Data synthesis Perfluorooctanoic acid (PFOA) does not occur naturally but is present in the serum of most residents of industrialized countries (U.S. median, 4 ng/mL). Drinking water is the primary route of exposure in some populations, but exposure sources are not well understood. PFOA has been used to manufacture such products as Gore-Tex and Teflon. PFOA does not break down in the environment; the human half-life is estimated at about 3 years. PFOA is not metabolized in the body; it is not lipophilic. PFOA is not directly genotoxic; animal data indicate that it can cause several types of tumors and neonatal death and may have toxic effects on the immune, liver, and endocrine systems. Data on the human health effects of PFOA are sparse. There is relatively consistent evidence of modest positive associations with cholesterol and uric acid, although the magnitude of the cholesterol effect is inconsistent across different exposure levels. There is some but much less consistent evidence of a modest positive correlation with liver enzymes. Most findings come from cross-sectional studies, limiting conclusions. Two occupational cohort studies do not provide consistent evidence for chronic disease; both are limited by sample size and reliance on mortality data. Reproductive data have increased recently but are inconsistent, and any observed adverse effects are modest. Conclusions Epidemiologic evidence remains limited, and to date data are insufficient to draw firm conclusions regarding the role of PFOA for any of the diseases of concern.

An overview of methods for calculating the burden of disease due to specific risk factors.

There are a number of measures that quantify the public health burden due to specific risk factors for specific diseases. Although these measures are of importance for policymakers, epidemiologists do not often calculate them or may be unfamiliar with some of the issues involved when they do. The primary measure of interest is the attributable fraction (AF), representing the fraction of cases or deaths from a specific disease that would not have occurred in the absence of exposure to a specific risk factor either in the exposed population or the population as a whole. AFs can be multiplied by the total number of cases of a given disease to obtain a “body count”—the absolute number of preventable cases due to a specific risk factor. Two other measures of public health burden, used in conjunction with AFs, are attributable years-of-life-lost and attributable disability-adjusted life-years. We provide an overview of the AF and related measures and discuss some of the specific issues involved in calculating AFs. These issues include calculating the variance of AFs (such as Monte Carlo sensitivity methods), biases arising from some formulas for the AF, sources of data for calculating AFs, dependence of AFs on basic decisions about what exposure–disease associations are causal, and extrapolation from the source population to the target population.

Rate of decline in serum PFOA concentrations after granular activated carbon filtration at two public water systems in Ohio and West Virginia.

Background Drinking water in multiple water districts in the Mid-Ohio Valley has been contaminated with perfluorooctanoic acid (PFOA), which was released by a nearby DuPont chemical plant. Two highly contaminated water districts began granular activated carbon filtration in 2007. Objectives To determine the rate of decline in serum PFOA, and its corresponding half-life, during the first year after filtration. Methods Up to six blood samples were collected from each of 200 participants from May 2007 until August 2008. The primary source of drinking water varied over time for some participants; our analyses were grouped according to water source at baseline in May–June 2007. Results For Lubeck Public Service District customers, the average decrease in serum PFOA concentrations between May–June 2007 and May–August 2008 was 32 ng/mL (26%) for those primarily consuming public water at home (n = 130), and 16 ng/mL (28%) for those primarily consuming bottled water at home (n = 17). For Little Hocking Water Association customers, the average decrease in serum PFOA concentrations between November–December 2007 and May–June 2008 was 39 ng/mL (11%) for consumers of public water (n = 39) and 28 ng/mL (20%) for consumers of bottled water (n = 11). The covariate-adjusted average rate of decrease in serum PFOA concentration after water filtration was 26% per year (95% confidence interval, 25–28% per year). Conclusions The observed data are consistent with first-order elimination and a median serum PFOA half-life of 2.3 years. Ongoing follow-up will lead to improved half-life estimation.

Association of Perfluorooctanoic Acid and Perfluorooctane Sulfonate With Serum Lipids Among Adults Living Near a Chemical Plant

Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are compounds that do not occur in nature but have been widely used since World War II and persist indefinitely in the environment. They are present in the serum of Americans with median levels of 4 ng/mL and 21 ng/mL, respectively. PFOA has been positively associated with cholesterol in several studies of workers. A cross-sectional study of lipids and PFOA and PFOS was conducted among 46,294 community residents aged 18 years or above, who drank water contaminated with PFOA from a chemical plant in West Virginia. The mean levels of serum PFOA and PFOS in 2005-2006 were 80 ng/mL (median, 27 ng/mL) and 22 ng/mL (median, 20 ng/mL), respectively. All lipid outcomes except high density lipoprotein cholesterol showed significant increasing trends by increasing decile of either compound; high density lipoprotein cholesterol showed no association. The predicted increase in cholesterol from lowest to highest decile for either compound was 11-12 mg/dL. The odds ratios for high cholesterol (>/=240 mg/dL), by increasing quartile of PFOA, were 1.00, 1.21 (95% confidence interval (CI): 1.12, 1.31), 1.33 (95% CI: 1.23, 1.43), and 1.40 (95% CI: 1.29, 1.51) and were similar for PFOS quartiles. Because these data are cross-sectional, causal inference is limited. Nonetheless, the associations between these compounds and lipids raise concerns, given their common presence in the general population.

A Practical Guide to Dose-Response Analyses and Risk Assessment in Occupational Epidemiology

Dose-response modeling in occupational epidemiology is usually motivated by questions of causal inference (eg, is there a monotonic increase of risk with increasing exposure?) or risk assessment (eg, how much excess risk exists at any given level of exposure?). We focus on several approaches to dose-response in occupational cohort studies. Categorical analyses are useful for detecting the shape of dose-response. However, they depend on the number and location of cutpoints and result in step functions rather than smooth curves. Restricted cubic splines and penalized splines are useful parametric techniques that provide smooth curves. Although splines can complement categorical analyses, they do not provide interpretable parameters. The shapes of these curves will depend on the degree of “smoothing” chosen by the analyst. We recommend combining categorical analyses and some type of smoother, with the goal of developing a reasonably simple parametric model. A simple parametric model should serve as the goal of dose-response analyses because (1) most “true” exposure response curves in nature may be reasonably simple, (2) a simple parametric model is easily communicated and used by others, and (3) a simple parametric model is the best tool for risk assessors and regulators seeking to estimate individual excess risks per unit of exposure. We discuss these issues and others, including whether the best model is always the one that fits the best, reasons to prefer a linear model for risk in the low-exposure region when conducting risk assessment, and common methods of calculating excess lifetime risk at a given exposure from epidemiologic results (eg, from rate ratios). Points are illustrated using data from a study of dioxin and cancer.

Perfluorooctanoic acid, perfluorooctanesulfonate, and serum lipids in children and adolescents: results from the C8 Health Project

BACKGROUND Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) are man-made compounds with widespread presence in human sera. In previous occupational and adult studies, PFOA and PFOS were positively associated with serum lipid levels. OBJECTIVE To interrogate associations between PFOA and PFOS and serum lipids in children and adolescents. DESIGN Cross-sectional community-based study. SETTING Mid-Ohio River Valley. PARTICIPANTS A total of 12 476 children and adolescents included in the C8 Health Project, which resulted from the pretrial settlement of a class action lawsuit pursuant to PFOA contamination of the drinking water supply. MAIN OUTCOME MEASURES Serum lipids (total, high-density lipoprotein [HDL-C], and low-density lipoprotein [LDL-C] cholesterol and fasting triglycerides). RESULTS Mean (SD) serum PFOA and PFOS concentrations were 69.2 (111.9) ng/mL and 22.7 (12.6) ng/mL, respectively. In linear regression after adjustment for covariables, PFOA was significantly associated with increased total cholesterol and LDL-C, and PFOS was significantly associated with increased total cholesterol, HDL-C, and LDL-C. Using general linear model analysis of covariance, between the first and fifth quintiles of PFOA there was a 4.6-mg/dL and a 3.8-mg/dL increase in the adjusted mean levels of total cholesterol and LDL-C levels, respectively, and an 8.5-mg/dL and a 5.8-mg/dL increase in the adjusted mean levels of total cholesterol and LDL-C, respectively, between the first and fifth quintiles of PFOS. Increases were 10 mg/dL for some age- and sex-group strata. Observed effects were nonlinear, with larger increases in total cholesterol and LDL-C levels occurring at the lowest range, particularly of PFOA. CONCLUSION Although the epidemiologic and cross-sectional natures of this study limit causal inferences, the consistently observed associations between increasing PFOA and PFOS and elevated total cholesterol and LDL-C levels warrant further study.

Association of Perfluorooctanoic Acid (PFOA) and Perfluorooctane Sulfonate (PFOS) with Uric Acid among Adults with Elevated Community Exposure to PFOA

Background Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) are compounds that do not occur in nature, have been widely used since World War II, and persist indefinitely in most environments. Median serum levels in the United States are 4 ng/mL for PFOA and 21 ng/mL for PFOS. PFOA has been associated with elevated uric acid in two studies of chemical workers. Uric acid is a risk factor for hypertension and possibly other cardiovascular outcomes. Methods We conducted a cross-sectional study of PFOA and PFOS and uric acid among 54,951 adult community residents in Ohio and West Virginia, who lived or worked in six water districts contaminated with PFOA from a chemical plant. Analyses were conducted by linear and logistic regression, adjusted for confounders. Results Both PFOA and PFOS were significantly associated with uric acid. An increase of 0.2–0.3 mg/dL uric acid was associated with an increase from the lowest to highest decile of either PFOA or PFOS. Hyperuricemia risk increased modestly with increasing PFOA; the odds ratios by quintile of PFOA were 1.00, 1.33 [95% confidence interval (CI), 1.24–1.43], 1.35 (95% CI, 1.26–1.45), 1.47 (95% CI, 1.37–1.58), and 1.47 (95% CI, 1.37–1.58; test for trend, p < 0.0001). We saw a less steep trend for PFOS. Inclusion of both correlated fluorocarbons in the model indicated PFOA was a more important predictor than was PFOS. Conclusion Higher serum levels of PFOA were associated with a higher prevalence of hyperuricemia, but the limitations of cross-sectional data and the possibility of noncausal mechanisms prohibit conclusions regarding causality.

Polychlorinated Biphenyls and Neurodegenerative Disease Mortality in an Occupational Cohort

Background: Production of polychlorinated biphenyls (PCBs) ended in the United States in the 1970s, but PCBs persist in the environment and are detectable in the blood of approximately 80% of Americans over age 50. PCBs decrease dopamine levels in rats and monkeys. Loss of dopamine is the hallmark of Parkinson disease, a neurodegenerative disease. There are no epidemiologic studies of PCBs and neurodegenerative disease. Methods: We conducted a retrospective mortality study of 17,321 PCB-exposed workers to determine whether mortality from Parkinson disease, dementia, and amyotrophic lateral sclerosis was elevated compared with the U.S. population. All workers had a least 90 days employment in 1 of 3 electrical capacitor plants using PCBs from the 1940s to the 1970s. PCB serum levels from a sample of these workers in the 1970s were approximately 10 times the level of community controls. Results: We found no overall excess of Parkinson disease, amyotrophic lateral sclerosis, or dementia in the PCB-exposed cohort (standardized mortality ratios [SMRs]-1.40, 1.11, and 1.26, respectively, and number of deaths-14, 10, and 28 respectively). However, sex-specific analyses revealed that women had an excess of amyotrophic lateral sclerosis (SMR-2.26; 95% confidence interval [CI] = 1.08–4.15; 10 deaths). Furthermore, among highly exposed women (defined by a job-exposure matrix), we found an excess of Parkinson disease (SMR-2.95; 95% CI = 1.08–6.42; 6 deaths) and dementia (SMR-2.04; 95% CI = 1.12–3.43; 14 deaths). Conclusions: Our data are limited due to small numbers and reliance on mortality rather than incidence data, but are suggestive of an effect of PCBs on neurodegenerative disease for women. The literature does not offer an explanation for why women would be more affected than men by PCB exposure for these outcomes.

Perfluorooctanoic Acid (PFOA) Exposures and Incident Cancers among Adults Living near a Chemical Plant

Background: Perfluorooctanoic acid (PFOA) is a synthetic chemical ubiquitous in the serum of U.S. residents. It causes liver, testicular, and pancreatic tumors in rats. Human studies are sparse. Objective: We examined cancer incidence in Mid-Ohio Valley residents exposed to PFOA in drinking water due to chemical plant emissions. Methods: The cohort consisted of adult community residents who resided in contaminated water districts or worked at a local chemical plant. Most participated in a 2005–2006 baseline survey in which serum PFOA was measured. We interviewed the cohort in 2008–2011 to obtain further medical history. Retrospective yearly PFOA serum concentrations were estimated for each participant from 1952 through 2011. Self-reported cancers were validated through medical records and cancer registry review. We estimated the association between cancer and cumulative PFOA serum concentration using proportional hazards models. Results: Participants (n = 32,254) reported 2,507 validated cancers (21 different cancer types). Estimated cumulative serum PFOA concentrations were positively associated with kidney and testicular cancer [hazard ratio (HR) = 1.10; 95% CI: 0.98, 1.24 and HR = 1.34; 95% CI: 1.00, 1.79, respectively, for 1-unit increases in ln-transformed serum PFOA]. Categorical analyses also indicated positive trends with increasing exposures for both cancers: for kidney cancer HRs for increasing exposure quartiles were 1.0, 1.23, 1.48, and 1.58 (linear trend test p = 0.18) and for testicular cancer, HRs were 1.0, 1.04, 1.91, 3.17 (linear trend test p = 0.04). Conclusions: PFOA exposure was associated with kidney and testicular cancer in this population. Because this is largely a survivor cohort, findings must be interpreted with caution, especially for highly fatal cancers such as pancreatic and lung cancer. Citation: Barry V, Winquist A, Steenland K. 2013. Perfluorooctanoic acid (PFOA) exposures and incident cancers among adults living near a chemical plant. Environ Health Perspect 121:1313–1318; http://dx.doi.org/10.1289/ehp.1306615