Systematic review and meta-analysis of birth weight and perfluorohexane sulfonate exposures: examination of sample timing and study confidence.

We examined the association between mean birth weight (BW) differences and perfluorohexane sulfonate (PFHxS) exposure biomarkers.We fit a random effects model to estimate the overall pooled effect and for different strata based on biomarker sample timing and overall study confidence. We also conducted an analysis to examine the impact of a continuous measure of gestational age sample timing on the overall pooled effect.We detected a -7.9 g (95% CI -15.0 to -0.7; pQ=0.85; I2=0%) BW decrease per ln ng/mL PFHxS increase based on 27 studies. The 11 medium confidence studies (ß=-10.0 g; 95% CI -21.1 to 1.1) showed larger deficits than 12 high (ß=-6.8 g; 95% CI -16.3 to 2.8) and 4 low confidence studies (ß=-1.5 g; 95% CI -51.6 to 48.7). 10 studies with mid-pregnancy to late-pregnancy sampling periods showed smaller deficits (ß=-3.9 g; 95% CI -17.7 to 9.9) than 5 post-partum studies (ß=-28.3 g; 95% CI -69.3 to 12.7) and 12 early sampling studies (ß=-7.6 g; 95% CI -16.2 to 1.1). 6 of 12 studies with the earliest sampling timing showed results closer to the null.Overall, we detected a small but statistically significant BW deficit across 27 studies. We saw comparable BW deficit magnitudes in both the medium and high confidence studies as well as the early pregnancy group. Despite no definitive pattern by sample timing, larger deficits were seen in postpartum studies. We also saw results closer to the null for a subset of studies restricted to the earliest biomarker collection times. Serial pregnancy sampling, improved precision in gestational age estimates and more standardised reporting of sample variation and exposure units in future epidemiologic research may offer a greater understanding of the relationship between PFHxS on BW and any potential impact of pregnancy haemodynamics.

A tool to assess risk of bias in non-randomized follow-up studies of exposure effects (ROBINS-E).

BACKGROUND: Observational epidemiologic studies provide critical data for the evaluation of the potential effects of environmental, occupational and behavioural exposures on human health. Systematic reviews of these studies play a key role in informing policy and practice. Systematic reviews should incorporate assessments of the risk of bias in results of the included studies. OBJECTIVE: To develop a new tool, Risk Of Bias In Non-randomized Studies - of Exposures (ROBINS-E) to assess risk of bias in estimates from cohort studies of the causal effect of an exposure on an outcome. METHODS AND RESULTS: ROBINS-E was developed by a large group of researchers from diverse research and public health disciplines through a series of working groups, in-person meetings and pilot testing phases. The tool aims to assess the risk of bias in a specific result (exposure effect estimate) from an individual observational study that examines the effect of an exposure on an outcome. A series of preliminary considerations informs the core ROBINS-E assessment, including details of the result being assessed and the causal effect being estimated. The assessment addresses bias within seven domains, through a series of 'signalling questions'. Domain-level judgements about risk of bias are derived from the answers to these questions, then combined to produce an overall risk of bias judgement for the result, together with judgements about the direction of bias. CONCLUSION: ROBINS-E provides a standardized framework for examining potential biases in results from cohort studies. Future work will produce variants of the tool for other epidemiologic study designs (e.g. case-control studies). We believe that ROBINS-E represents an important development in the integration of exposure assessment, evidence synthesis and causal inference.

Comparative susceptibility of children and adults to neurological effects of inhaled manganese: A review of the published literature.

BACKGROUND: Manganese (Mn) is neurotoxic in adults and children. Current assessments are based on the more extensive adult epidemiological data, but the potential for greater childhood susceptibility remains a concern. To better understand potential lifestage-based variations, we compared susceptibilities to neurotoxicity in children and adults using Mn biomarker data. METHODS: We developed a literature search strategy based on a Population, Exposures, Comparators, and Outcomes statement focusing on inhalation exposures and neurological outcomes in humans. Screening was performed using DistillerSR. Hair biomarker studies were selected for evaluation because studies with air measurements were unavailable or considered inadequate for children. Studies were paired based on concordant Mn source, biomarker, and outcome. Comparisons were made based on reported dose-response slopes (children vs. adults). Study evaluation was conducted to understand the confidence in our comparisons. RESULTS: We identified five studies evaluating seven pairings of hair Mn and neurological outcomes (cognition and motor effects) in children and adults matched on sources of environmental Mn inhalation exposure. Two Brazilian studies of children and one of adults reported intelligent quotient (IQ) effects; effects in both comparisons were stronger in children (1.21 to 2.03-fold difference). In paired analyses of children and adults from the United States, children exhibited both stronger and weaker effects compared to adults (0.37 to 1.75-fold differences) on postural sway metrics. CONCLUSION: There is limited information on the comparative susceptibility of children and adults to inhaled Mn. We report that children may be 0.37 to 2.03 times as susceptible as adults to neurotoxic effects of Mn, thereby providing a quantitative estimate for some aspects of lifestage variation. Due to the limited number of paired studies available in the literature, this quantitative estimate should be interpreted with caution. Our analyses do not account for other sources of inter-individual variation. Additional studies of Mn-exposed children with direct air concentration measurements would improve the evidence base.

The effect of age on the relative risk of lung cancer mortality in a cohort of chromium production workers.

BACKGROUND: Hexavalent chromium has been found to increase the risk of lung cancer in occupational studies. It has been suggested that the relative risk of lung cancer may vary by age. METHODS: The cohort examined is the Baltimore cohort of chromium production workers. The effect of age on the lung cancer risk from hexavalent chromium exposure was examined using a conditional Poisson regression modeling approach of Richardson and Langholz (R&L) and Cox models with interaction terms of age and cumulative hexavalent chromium exposure. RESULTS: The inclusion of multiple age groups in the R&L approach suggests the existence of an age effect that is also supported by a Cox proportional hazard analysis. The hazard ratio in Cox models with age-cumulative exposure interaction terms was significantly elevated for the youngest age group and significantly decreased for the oldest age group. CONCLUSIONS: Our analyses are consistent with the observation that younger chromium production workers have a greater lung cancer risk than older workers.

Methods for evaluating variability in human health dose-response characterization.

The Reference Dose (RfD) and Reference Concentration (RfC) are human health reference values (RfVs) representing exposure concentrations at or below which there is presumed to be little risk of adverse effects in the general human population. The 2009 National Research Council report Science and Decisions recommended redefining RfVs as "a risk-specific dose (for example, the dose associated with a 1 in 100,000 risk of a particular end point)." Distributions representing variability in human response to environmental contaminant exposures are critical for deriving risk-specific doses. Existing distributions estimating the extent of human toxicokinetic and toxicodynamic variability are based largely on controlled human exposure studies of pharmaceuticals. New data and methods have been developed that are designed to improve estimation of the quantitative variability in human response to environmental chemical exposures. Categories of research with potential to provide new database useful for developing updated human variability distributions include controlled human experiments, human epidemiology, animal models of genetic variability, in vitro estimates of toxicodynamic variability, and in vitro-based models of toxicokinetic variability. In vitro approaches, with further development including studies of different cell types and endpoints, and approaches to incorporate non-genetic sources of variability, appear to provide the greatest opportunity for substantial near-term advances.

Epidemiology: a foundation of environmental decision making.

Many epidemiologic studies are designed so they can be drawn upon to provide scientific evidence for evaluating hazards of environmental exposures, conducting quantitative assessments of risk, and informing decisions designed to reduce or eliminate harmful exposures. However, experimental animal studies are often relied upon for environmental and public health policy making despite the expanding body of observational epidemiologic studies that could inform the relationship between actual, as opposed to controlled, exposures and health effects. This paper provides historical examples of how epidemiology has informed decisions at the U.S. Environmental Protection Agency, discusses some challenges with using epidemiology to inform decision making, and highlights advances in the field that may help address these challenges and further the use of epidemiologic studies moving forward.

Human exposure to carbon-based fibrous nanomaterials: A review.

In an emerging field of nanotechnologies, assessment of exposure to carbon nanotubes (CNT) and carbon nanofibers (CNF) is an integral component of occupational and environmental epidemiology, risk assessment and management, as well as regulatory actions. The current state of knowledge on exposure to carbon-based fibrous nanomaterials among workers, consumers and general population was studied in frame of the International Agency for Research on Cancer (IARC) Monographs-Volume 111 "Some Nanomaterials and Some Fibres". Completeness and reliability of available exposure data for use in epidemiology and risk assessment were assessed. Occupational exposure to CNT/CNF may be of concern at all stages of the material life-cycle from research through manufacture to use and disposal. Consumer and environmental exposures are only estimated by modeled data. The available information of the final steps of the life-cycle of these materials remains incomplete so far regarding amounts of handled materials and levels of exposure. The quality and amount of information available on the uses and applications of CNT/CNF should be improved to enable quantitative assessment of human exposure to these materials. For that, coordinated effort in producing surveys and exposure inventories based on harmonized strategy of material test, exposure measurement and reporting results is strongly encouraged.

Influence of exposure assessment and parameterization on exposure response. Aspects of epidemiologic cohort analysis using the Libby Amphibole asbestos worker cohort.

Recent meta-analyses of occupational epidemiology studies identified two important exposure data quality factors in predicting summary effect measures for asbestos-associated lung cancer mortality risk: sufficiency of job history data and percent coverage of work history by measured exposures. The objective was to evaluate different exposure parameterizations suggested in the asbestos literature using the Libby, MT asbestos worker cohort and to evaluate influences of exposure measurement error caused by historically estimated exposure data on lung cancer risks. Focusing on workers hired after 1959, when job histories were well-known and occupational exposures were predominantly based on measured exposures (85% coverage), we found that cumulative exposure alone, and with allowance of exponential decay, fit lung cancer mortality data similarly. Residence-time-weighted metrics did not fit well. Compared with previous analyses based on the whole cohort of Libby workers hired after 1935, when job histories were less well-known and exposures less frequently measured (47% coverage), our analyses based on higher quality exposure data yielded an effect size as much as 3.6 times higher. Future occupational cohort studies should continue to refine retrospective exposure assessment methods, consider multiple exposure metrics, and explore new methods of maintaining statistical power while minimizing exposure measurement error.

Evaluating uncertainty to strengthen epidemiologic data for use in human health risk assessments.

BACKGROUND: There is a recognized need to improve the application of epidemiologic data in human health risk assessment especially for understanding and characterizing risks from environmental and occupational exposures. Although there is uncertainty associated with the results of most epidemiologic studies, techniques exist to characterize uncertainty that can be applied to improve weight-of-evidence evaluations and risk characterization efforts. METHODS: This report derives from a Health and Environmental Sciences Institute (HESI) workshop held in Research Triangle Park, North Carolina, to discuss the utility of using epidemiologic data in risk assessments, including the use of advanced analytic methods to address sources of uncertainty. Epidemiologists, toxicologists, and risk assessors from academia, government, and industry convened to discuss uncertainty, exposure assessment, and application of analytic methods to address these challenges. SYNTHESIS: Several recommendations emerged to help improve the utility of epidemiologic data in risk assessment. For example, improved characterization of uncertainty is needed to allow risk assessors to quantitatively assess potential sources of bias. Data are needed to facilitate this quantitative analysis, and interdisciplinary approaches will help ensure that sufficient information is collected for a thorough uncertainty evaluation. Advanced analytic methods and tools such as directed acyclic graphs (DAGs) and Bayesian statistical techniques can provide important insights and support interpretation of epidemiologic data. CONCLUSIONS: The discussions and recommendations from this workshop demonstrate that there are practical steps that the scientific community can adopt to strengthen epidemiologic data for decision making.

Low levels of exposure to libby amphibole asbestos and localized pleural thickening.

OBJECTIVE: To explore the relationship between low levels of exposure to Libby amphibole asbestos (LAA) and pleural abnormalities, specifically localized pleural thickening (LPT). METHODS: Three studies presenting the risks associated with quantitative LAA exposure estimates were reviewed, paying particular attention to lower exposure ranges. RESULTS: Studies reviewed were conducted among workers exposed to LAA at mining and milling operations in Libby, Montana, at a vermiculite processing facility in Marysville, Ohio, and community residents exposed to LAA from a vermiculite processing facility in Minneapolis, Minnesota. Pleural abnormalities were evaluated using radiographs. Despite differences in study populations and design, each study found that cumulative inhalation LAA exposure was associated with increased risk of LPT even at low levels of exposure. CONCLUSIONS: Inhalation exposure to LAA is associated with increased risk of LPT even at the lowest levels of exposure in each study.

Increased risk of cancer mortality associated with cadmium exposures in older Americans with low zinc intake.

Cadmium (Cd) exposure has been associated with increased cancer risk, and zinc (Zn) appears to reduce that risk. However, little is known about the combined influence of Cd and Zn on cancer risk. The aim of this study was to examine relationships between Cd exposure, Zn intake, and cancer mortality risks. The analyses used 5204 subjects aged 50 yr or older from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) and the mortality follow-up through December 31, 2006. Cox proportional hazards models were used to test associations. In total, 569 cancer deaths were recorded during an average follow-up of 12.4 yr, including 155 from lung, 61 from prostate, and 26 from breast cancer. A positive association between Cd and cancer mortality risk was identified for both genders. Despite limited cause-specific deaths, the increased risk associated with Cd was significant for lung cancer in men. All-cause cancer mortality risk was significantly elevated among women with Zn intakes below the recommended dietary allowance (RDA) compared with women who met the RDA. The effect of low dietary Zn was not observed in men. Similar trends for prostate and breast cancer deaths were not significant. There was a significant inverse association between cancer deaths and the Zn-to-Cd ratio for both genders. Cd exposure is an important independent risk factor of cancer mortality in older Americans and the risk appears exaggerated in those with inadequate dietary Zn. Additional studies are required to elucidate the mechanism(s) by which Zn participates in the carcinogenic influence of Cd.

A review of the genotoxicity of 1,2-dichloroethane (EDC).

1,2-Dichloroethane (EDC, CAS#107-06-2) is a high production volume halogenated aliphatic hydrocarbon that is used mainly in the manufacture of vinyl chloride. EDC has been found in ambient and residential air samples, as well as in groundwater, surface water and drinking water. EDC has been well-studied in a variety of genotoxicity assays, and appears to involve the metabolic activation of the parent compound. We critically evaluated the genotoxicity data of EDC and its metabolites as part of an evaluation of carcinogenic mechanisms of action of EDC. EDC is genotoxic in multiple test systems via multiple routes of exposure. EDC has been shown to induce DNA adduct formation, gene mutations and chromosomal aberrations in the presence of key activation enzymes (including CYP450s and/or GSTs) in laboratory animal and in vitro studies. EDC was negative for clastogenesis as measured by the micronucleus assay in mice. In general, an increased level of DNA damage is observed related to the GSH-dependent bioactivation of EDC. Increased chromosomal aberrations with increased CYP450 expression were suggestive of a role for the oxidative metabolites of EDC in inducing chromosomal damage. Taken together, these studies demonstrate that EDC exposure, in the presence of key enzymes (including CYP450s and/or GSTs), leads to DNA adduct formation, gene mutations and chromosomal aberrations.

Regression calibration for classical exposure measurement error in environmental epidemiology studies using multiple local surrogate exposures.

Environmental epidemiologic studies are often hierarchical in nature if they estimate individuals' personal exposures using ambient metrics. Local samples are indirect surrogate measures of true local pollutant concentrations which estimate true personal exposures. These ambient metrics include classical-type nondifferential measurement error. The authors simulated subjects' true exposures and their corresponding surrogate exposures as the mean of local samples and assessed the amount of bias attributable to classical and Berkson measurement error on odds ratios, assuming that the logit of risk depends on true individual-level exposure. The authors calibrated surrogate exposures using scalar transformation functions based on observed within- and between-locality variances and compared regression-calibrated results with naive results using surrogate exposures. The authors further assessed the performance of regression calibration in the presence of Berkson-type error. Following calibration, bias due to classical-type measurement error, resulting in as much as 50% attenuation in naive regression estimates, was eliminated. Berkson-type error appeared to attenuate logistic regression results less than 1%. This regression calibration method reduces effects of classical measurement error that are typical of epidemiologic studies using multiple local surrogate exposures as indirect surrogate exposures for unobserved individual exposures. Berkson-type error did not alter the performance of regression calibration. This regression calibration method does not require a supplemental validation study to compute an attenuation factor.

Exposure to asbestos-containing vermiculite ore and respiratory symptoms among individuals who were children while the mine was active in Libby, Montana.

BACKGROUND: Libby, Montana, was home to the largest vermiculite ore mine in the United States. The processing, use, and transport of the ore, which was contaminated with amphibole asbestos, led to generalized contamination of the community. The mine closed in 1990. OBJECTIVES: We examined the prevalence of respiratory symptoms in 2000-2001 and their association with history of vermiculite exposure among people who were < or = 18 years of age when the mine closed. METHODS: Information on respiratory symptoms and exposure history was collected by questionnaire in 2000-2001, at which time participants were 10-29 years old. Logistic regression was used to model the associations between exposures and outcomes adjusted for age, sex, and tobacco smoke exposure. RESULTS: Of the 1,003 individuals included in the study, 10.8% reported usually having a cough, 14.5% reported experiencing shortness of breath when walking up a slight hill or hurrying on level ground, and 5.9% reported having coughed up bloody phlegm in the past year. These respiratory symptoms were positively associated with frequently handling vermiculite insulation compared with never handling vermiculite insulation. We found no association between vermiculite insulation in the house and respiratory symptoms. Respiratory symptoms were associated with other vermiculite exposures as well, and the number and frequency of these activities showed a positive trend with usually having a cough. We found no association between any of the activities and abnormal spirometry. CONCLUSIONS: These data suggest that residents of Libby, Montana, who were children when the mine closed experienced some respiratory symptoms associated with asbestos-contaminated vermiculite exposure.

A reexamination of the PPAR-alpha activation mode of action as a basis for assessing human cancer risks of environmental contaminants.

BACKGROUND: Diverse environmental contaminants, including the plasticizer di(2-ethylhexyl)phthalate (DEHP), are hepatocarcinogenic peroxisome proliferators in rodents. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activation and its sequelae have been proposed to constitute a mode of action (MOA) for hepatocarcinogenesis by such agents as a sole causative factor. Further, based on a hypothesized lower sensitivity of humans to this MOA, prior reviews have concluded that rodent hepatocarcinogenesis by PPAR-alpha agonists is irrelevant to human carcinogenic risk. DATA SYNTHESIS: Herein, we review recent studies that experimentally challenge the PPAR-alpha activation MOA hypothesis, providing evidence that DEHP is hepatocarcinogenic in PPAR-alpha-null mice and that the MOA but not hepatocarcinogenesis is evoked by PPAR-alpha activation in a transgenic mouse model. We further examine whether relative potency for PPAR-alpha activation or other steps in the MOA correlates with tumorigenic potency. In addition, for most PPAR-alpha agonists of environmental concern, available data are insufficient to characterize relative human sensitivity to this rodent MOA or to induction of hepatocarcinogenesis. CONCLUSIONS: Our review and analyses raise questions about the hypothesized PPAR-alpha activation MOA as a sole explanation for rodent hepatocarcinogenesis by PPAR-alpha agonists and therefore its utility as a primary basis for assessing human carcinogenic risk from the diverse compounds that activate PPAR-alpha. These findings have broad implications for how MOA hypotheses are developed, tested, and applied in human health risk assessment. We discuss alternatives to the current approaches to these key aspects of mechanistic data evaluation.

Effects of exposure to 0.06 ppm ozone on FEV1 in humans: a secondary analysis of existing data.

BACKGROUND: Ozone is a potent photochemical oxidant that produces transient, reversible decrements in the lung function of acutely exposed individuals. A recent study provided previously unavailable clinical data for 30 healthy young adults exposed to O(3) at 0.06 ppm. That study showed significant effects of 0.08 ppm on lung function, confirming the findings of others. However, exposure to 0.06 ppm O(3) was not reported to significantly affect lung function. OBJECTIVES: We conducted this analysis to reevaluate the existing lung function data of the volunteers previously exposed to 0.06 ppm O(3). METHODS: We obtained pre- and postexposure data on forced expiratory volume in 1 sec (FEV(1)) for all subjects who were previously exposed for 6.6 hr to filtered air or to 0.06 ppm or 0.08 ppm O(3). We used standard statistical methods appropriate for paired comparisons to reanalyze FEV(1) responses after exposure to 0.06 ppm O(3) relative to filtered air. RESULTS: Controlling for filtered air responses, 24 of the 30 subjects experienced an O(3)-induced decrement in FEV(1). On average, 0.06 ppm O(3) exposure caused a 2.85% reduction in FEV(1) (p < 0.002), which was consistent with the predicted FEV(1) response from existing models. Although the average response was small, two subjects had > 10% FEV(1) decrements. CONCLUSIONS: Exposure to 0.06 ppm O(3) causes a biologically small but highly statistically significant decrease in mean FEV(1) responses of young healthy adults.

Children's response to air pollutants.

It is important to focus on children with respect to air pollution because (1) their lungs are not completely developed, (2) they can have greater exposures than adults, and (3) those exposures can deliver higher doses of different composition that may remain in the lung for greater duration. The undeveloped lung is more vulnerable to assault and less able to fully repair itself when injury disrupts morphogenesis. Children spend more time outside, where concentrations of combustion-generated air pollution are generally higher. Children have higher baseline ventilation rates and are more physically active than adults, thus exposing their lungs to more air pollution. Nasal breathing in adults reduces some pollution concentrations, but children are more typically mouth-breathers--suggesting that the composition of the exposure mixture at the alveolar level may be different. Finally, higher ventilation rates and mouth-breathing may pull air pollutants deeper into children's lungs, thereby making clearance slower and more difficult. Children also have immature immune systems, which plays a significant role in asthma. The observed consequences of early life exposure to adverse levels of air pollutants include diminished lung function and increased susceptibility to acute respiratory illness and asthma. Exposure to diesel exhaust, in particular, is an area of concern for multiple endpoints, and deserves further research.

Smallpox vaccination and ischemic coronary events in healthy adults.

Although smallpox vaccine-associated myopericarditis has been reported, the risk of cardiac ischemic events remains uncertain. We identified personnel receiving the smallpox vaccination and compared them to a historical referent population. The rate of cardiac ischemia diagnoses in the 30 days following smallpox vaccination was 140.1 per 100,000 person-years, compared to 143.5 per 100,000 person-years in referent group (RR 1.0 [95% CI: 0.7-1.4]). The rate of cardiac ischemic events in vaccinees was 121.4 per 100,000 person-years before and 175.7 after adopting pre-vaccination cardiac screening (RR 1.4 [95% CI: 0.8-2.7]). Implementation of pre-vaccination cardiac risk factor screening was not associated with a reduction in cardiac events.