Can Incorrect Analysis of Time-Dependent Exposure Explain Associations between PM2.5 Exposure and Risk of Dementia?

Background: Epidemiological studies have reported positive associations between long-term exposure to particulate matter of 2.5 microns or less in diameter (PM2.5) and risk of Alzheimer's disease and other clinical dementia. Many of these studies have analyzed data using Cox Proportional Hazards (PH) regression, which estimates a hazard ratio (HR) for the treatment (in this case, exposure) effect on the time-to-event outcome while adjusting for influential covariates. PM2.5 levels vary over time. As air quality standards for PM2.5 have become more stringent over time, average outdoor PM2.5 levels have decreased substantially. Objective: Investigate whether a Cox PH analysis that does not properly account for exposure that varies over time could produce a biased HR of similar magnitude to the HRs reported in recent epidemiological studies of PM2.5 and dementia risk. Methods: Simulation analysis. Results: We found that the biased HR can affect statistical analyses that consider exposure levels at event times only, especially if PM2.5 levels decreased consistently over time. Furthermore, the direction of such bias is away from the null and of a magnitude that is consistent with the reported estimates of dementia risk in several epidemiological studies of PM2.5 exposure (HR≈1.2 to 2.0). Conclusions: This bias can be avoided by correctly assigning exposure to study subjects throughout the entire follow-up period. We recommend that investigators provide a detailed description of how time-dependent exposure variables were accounted for in their Cox PH analyses when they report their results.

Range of the perfluorooctanoate (PFOA) safe dose for human health: An international collaboration.

Many government agencies and expert groups have estimated a dose-rate of perfluorooctanoate (PFOA) that would protect human health. Most of these evaluations are based on the same studies (whether of humans, laboratory animals, or both), and all note various uncertainties in our existing knowledge. Nonetheless, the values of these various, estimated, safe-doses vary widely, with some being more than 100,000 fold different. This sort of discrepancy invites scrutiny and explanation. Otherwise what is the lay public to make of this disparity? The Steering Committee of the Alliance for Risk Assessment (2022) called for scientists interested in attempting to understand and narrow these disparities. An advisory committee of nine scientists from four countries was selected from nominations received, and a subsequent invitation to scientists internationally led to the formation of three technical teams (for a total of 24 scientists from 8 countries). The teams reviewed relevant information and independently developed ranges for estimated PFOA safe doses. All three teams determined that the available epidemiologic information could not form a reliable basis for a PFOA safe dose-assessment in the absence of mechanistic data that are relevant for humans at serum concentrations seen in the general population. Based instead on dose-response data from five studies of PFOA-exposed laboratory animals, we estimated that PFOA dose-rates 10-70 ng/kg-day are protective of human health.

Integration of Evidence on Community Cancer Risks from Elongate Mineral Particles in Silver Bay, Minnesota.

The potential for cancer-related risks to community members from ambient exposure to elongate mineral particles (EMPs) in taconite processing has not been formally evaluated. We evaluated 926 ambient air samples including 12,928 EMPs (particle structures with length-to-width ratio ≥3:1) collected over 26 years near a taconite processing facility in Silver Bay, Minnesota. Eighty-two percent of EMPs were ≤3 µm in length and 97% of EMPs had an average aspect ratio <20:1. A total of 935 (7.3%) EMPs had length >5 µm and AR ≥3:1. Average ambient concentration of NIOSH countable amphibole EMPs over all years was 0.000387 EMPs per cubic centimeter (EMP/cm3 ). Of 12,765 nonchrysotile EMPs, the number of amphiboles with length and width dimensions that correlate best with asbestos-related carcinogenicity ranged from four (0.03%) to 13 (0.1%) and the associated ambient amphibole air concentrations ranged from 0.000003 to 0.000007 EMP/cm3 . After 65 years of taconite processing in Silver Bay, evidence of an increased risk of mesothelioma and lung cancer in community members who did not work in the taconite industry is lacking. The absence of an increased risk of asbestos-related cancer in the Silver Bay community is coherent with supporting evidence from epidemiological and toxicological studies, as well as ambient exposure data and lake sediment data collected in Minnesota Iron Range communities. Collectively, the data provide consistent evidence that nonasbestiform amphibole minerals lack the carcinogenic potential exhibited by amphibole asbestos.

Peak Exposures in Epidemiologic Studies and Cancer Risks: Considerations for Regulatory Risk Assessment.

We review approaches for characterizing "peak" exposures in epidemiologic studies and methods for incorporating peak exposure metrics in dose-response assessments that contribute to risk assessment. The focus was on potential etiologic relations between environmental chemical exposures and cancer risks. We searched the epidemiologic literature on environmental chemicals classified as carcinogens in which cancer risks were described in relation to "peak" exposures. These articles were evaluated to identify some of the challenges associated with defining and describing cancer risks in relation to peak exposures. We found that definitions of peak exposure varied considerably across studies. Of nine chemical agents included in our review of peak exposure, six had epidemiologic data used by the U.S. Environmental Protection Agency (US EPA) in dose-response assessments to derive inhalation unit risk values. These were benzene, formaldehyde, styrene, trichloroethylene, acrylonitrile, and ethylene oxide. All derived unit risks relied on cumulative exposure for dose-response estimation and none, to our knowledge, considered peak exposure metrics. This is not surprising, given the historical linear no-threshold default model (generally based on cumulative exposure) used in regulatory risk assessments. With newly proposed US EPA rule language, fuller consideration of alternative exposure and dose-response metrics will be supported. "Peak" exposure has not been consistently defined and rarely has been evaluated in epidemiologic studies of cancer risks. We recommend developing uniform definitions of "peak" exposure to facilitate fuller evaluation of dose response for environmental chemicals and cancer risks, especially where mechanistic understanding indicates that the dose response is unlikely linear and that short-term high-intensity exposures increase risk.

Cancer Risk Associated With Exposure to Bitumen and Bitumen Fumes: An Updated Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate whether cancer risks are increased among bitumen (asphalt) workers. METHODS: Systematic review and meta-analysis of cancer risks (lung, upper aerodigestive tract (UADT), esophagus, bladder, kidney, stomach, and skin) and bitumen exposure. Certainty in the epidemiological evidence that bitumen-exposed workers experience increased cancer risks was rated using Grading of Recommendations Assessment, Development and Evaluation criteria. RESULTS: After excluding lower-quality studies, lung cancer risks were not increased among bitumen-exposed workers (meta-relative risk [RR] 0.94, 95% CI 0.74 to 1.20, eight studies). Increased risks of UADT and stomach cancers were observed (meta-RR 1.31, 95% CI 1.03 to 1.67, 10 studies and meta-RR 1.29, 95% CI 1.03 to 1.62, seven studies, respectively). CONCLUSIONS: Except for lung cancer, evidence for increased cancer risks among bitumen-exposed workers was judged to be of low certainty, due to inadequate exposure characterization and unmeasured confounders (coal tar exposure, smoking, and alcohol consumption).

Six years after the NRC review of EPA's Draft IRIS Toxicological Review of Formaldehyde: Regulatory implications of new science in evaluating formaldehyde leukemogenicity.

Shortly after the International Agency for Research on Cancer (IARC) determined that formaldehyde causes leukemia, the United States Environmental Protection Agency (EPA) released its Draft IRIS Toxicological Review of Formaldehyde ("Draft IRIS Assessment"), also concluding that formaldehyde causes leukemia. Peer review of the Draft IRIS Assessment by a National Academy of Science committee noted that "causal determinations are not supported by the narrative provided in the draft" (NRC 2011). They offered recommendations for improving the Draft IRIS assessment and identified several important research gaps. Over the six years since the NRC peer review, significant new science has been published. We identify and summarize key recommendations made by NRC and map them to this new science, including extended analysis of epidemiological studies, updates of earlier occupational cohort studies, toxicological experiments using a sensitive mouse strain, mechanistic studies examining the role of exogenous versus endogenous formaldehyde in bone marrow, and several critical reviews. With few exceptions, new findings are consistently negative, and integration of all available evidence challenges the earlier conclusions that formaldehyde causes leukemia. Given formaldehyde's commercial importance, environmental ubiquity and endogenous production, accurate hazard classification and risk evaluation of whether exposure to formaldehyde from occupational, residential and consumer products causes leukemia are critical.

Does occupational exposure to formaldehyde cause hematotoxicity and leukemia-specific chromosome changes in cultured myeloid progenitor cells?

Several cross-sectional studies of a single population of workers exposed to formaldehyde at one of two factories using or producing formaldehyde-melamine resins in China have concluded that formaldehyde exposure induces damage to hematopoietic cells that originate in the bone marrow. Moreover, the investigators interpret observed differences between groups as evidence that formaldehyde induces myeloid leukemias, although the mechanisms for inducing these diseases are not obvious and recently published scientific findings do not support causation. Our objective was to evaluate hematological parameters and aneuploidy in relation to quantitative exposure measures of formaldehyde. We obtained the study data for the original study (Zhang et al. 2010 ) and performed linear regression analyses. Results showed that differences in white blood cell, granulocyte, platelet, and red blood cell counts are not exposure dependent. Among formaldehyde-exposed workers, no association was observed between individual average formaldehyde exposure estimates and frequency of aneuploidy, suggested by the original study authors to be indicators of myeloid leukemia risk.

Quantitative estimated exposure to vinyl chloride and risk of angiosarcoma of the liver and hepatocellular cancer in the US industry-wide vinyl chloride cohort: mortality update through 2013.

OBJECTIVE: To evaluate mortality risks of angiosarcoma of the liver (ASL), primary hepatocellular carcinoma (HCC) and other cancers among 9951 men employed between 1942 and 1972 at 35 US vinyl chloride (VC) or polyvinyl chloride plants followed for mortality through 31 December 2013. METHODS: SMR and time-dependent Cox proportional hazards analyses were used to evaluate mortality risks by cumulative VC exposure. RESULTS: Liver cancer mortality was elevated (SMR=2.87, 95% CI 2.40 to 3.40), and ASL and HCC were strongly associated with cumulative VC exposure ≥865 parts per million-years (ppm-years) (ASL: HR=36.3, 95% CI 13.1 to 100.5; and HCC: HR=5.3, 95% CI 1.6 to 17.7 for ≥2271 ppm-years). Excess deaths due to connective and soft tissue cancers (SMR=2.43, 95% CI 1.48 to 3.75), mesothelioma (SMR=2.29, 95% CI 1.18 to 4.00) and explosions (SMR=3.43, 95% CI 1.25 to 7.47) were seen. Mortalities due to melanoma, brain cancer, lung cancer and non-Hodgkin's lymphoma were not increased or associated with VC exposure. CONCLUSION: The association between VC and ASL first reported in this cohort 44 years ago persisted and was strongest among workers most highly exposed. VC exposure also was associated with HCC mortality, although it remains possible that misdiagnosis of early ASLs influenced findings.

Meta-Analysis of Cardiac Mortality in Three Cohorts of Carbon Black Production Workers.

Epidemiological studies have demonstrated associations between airborne environmental particle exposure and cardiac disease and mortality; however, few have examined such effects from poorly soluble particles of low toxicity such as manufactured carbon black (CB) particles in the work place. We combined standardised mortality ratio (SMR) and Cox proportional hazards results from cohort studies of US, UK and German CB production workers. Under a common protocol, we analysed mortality from all causes, heart disease (HD), ischemic heart disease (IHD) and acute myocardial infarction (AMI). Fixed and random effects (RE) meta-regression models were fit for employment duration, and for overall cumulative and lugged quantitative CB exposure estimates. Full cohort meta-SMRs (RE) were 1.01 (95% confidence interval (CI) 0.79-1.29) for HD; 1.02 (95% CI 0.80-1.30) for IHD, and 1.08 (95% CI 0.74-1.59) for AMI mortality. For all three outcomes, meta-SMRs were heterogeneous, increased with time since first and time since last exposure, and peaked after 25-29 or 10-14 years, respectively. Meta-Cox coefficients showed no association with lugged duration of exposure. A small but imprecise increased AMI mortality risk was suggested for cumulative exposure (RE-hazards ratio (HR) = 1.10 per 100 mg/m³-years; 95% CI 0.92-1.31), but not for lugged exposures. Our results do not demonstrate that airborne CB exposure increases all-cause or cardiac disease mortality.

Assessment of blood lead level declines in an area of historical mining with a holistic remediation and abatement program.

UNLABELLED: Lead exposure and blood lead levels (BLLs) in the United States have declined dramatically since the 1970s as many widespread lead uses have been discontinued. Large scale mining and mineral processing represents an additional localized source of potential lead exposure in many historical mining communities, such as Butte, Montana. After 25 years of ongoing remediation efforts and a residential metals abatement program that includes blood lead monitoring of Butte children, examination of blood lead trends offers a unique opportunity to assess the effectiveness of Butte's lead source and exposure reduction measures. This study examined BLL trends in Butte children ages 1-5 (n= 2796) from 2003-2010 as compared to a reference dataset matched for similar demographic characteristics over the same period. Blood lead differences across Butte during the same period are also examined. Findings are interpreted with respect to effectiveness of remediation and other factors potentially contributing to ongoing exposure concerns. REFERENCE POPULATION COMPARISON: BLLs from Butte were compared with a reference dataset (n=2937) derived from the National Health and Nutrition Examination Survey. The reference dataset was initially matched for child age and sample dates. Additional demographic factors associated with higher BLLs were then evaluated. Weights were applied to make the reference dataset more consistent with the Butte dataset for the three factors that were most disparate (poverty-to-income ratio, house age, and race/ethnicity). A weighted linear mixed regression model showed Butte geometric mean BLLs were higher than reference BLLs for 2003-2004 (3.48vs. 2.05µg/dL), 2005-2006 (2.65vs. 1.80µg/dL), and 2007-2008 (2.2vs. 1.72µg/dL), but comparable for 2009-2010 (1.53vs. 1.51µg/dL). This trend suggests that, over time, the impact of other factors that may be associated with Butte BLLs has been reduced. COMPARISON ACROSS BUTTE: Neighborhood differences were examined by dividing the Butte dataset into the older area called "Uptown", located at higher elevation atop historical mine workings, and "the Flats", at lower elevation and more recently developed. Significant declines in BLLs were observed over time in both areas, though Uptown had slightly higher BLLs than the Flats (2003-2004: 3.57vs. 3.45µg/dL, p=0.7; 2005-2006: 2.84vs. 2.52µg/dL, p=0.1; 2007-2008: 2.58vs. 1.99µg/dL, p=0.001; 2009-2010: 1.71vs. 1.44µg/dL, p=0.02). BLLs were higher when tested in summer/fall than in winter/spring for both neighborhoods, and statistically higher BLLs were found for children in Uptown living in properties built before 1940. Neighborhood differences and the persistence of a greater percentage of high BLLs (>5µg/dL) in Butte vs. the reference dataset support continuation of the home lead abatement program. CONCLUSIONS: Butte BLL declines likely reflect the cumulative effectiveness of screening efforts, community-wide remediation, and the ongoing metals abatement program in Butte in addition to other factors not accounted for by this study. As evidenced in Butte, abatement programs that include home evaluations and assistance in addressing multiple sources of lead exposure can be an important complement to community-wide soil remediation activities.

Cohort Study of Carbon Black Exposure and Risk of Malignant and Nonmalignant Respiratory Disease Mortality in the US Carbon Black Industry.

OBJECTIVE: To evaluate lung cancer and respiratory disease mortality associations with cumulative inhalable carbon black exposure among 6634 US carbon black workers. METHODS: This analysis was performed using standardized mortality ratio (SMRs) and Cox regression analyses. RESULTS: Lung cancer mortality was decreased overall (SMR = 0.77; 95% confidence interval [CI], 0.67 to 0.89) but less so among hourly male workers (SMR = 0.87; 95% CI, 0.71 to 1.05). No exposure-response association was observed with time-dependent cumulative inhalable carbon black: hazard ratio [HR] = 1.0 (95% CI, 0.6 to 1.6) for 20 to less than 50 mg/m·yr); HR = 1.3 (95% CI, 0.8 to 2.1) for 50 to less than 100 mg/m·yr; and HR = 1.4 (95% CI, 0.9 to 2.1) for 100 mg/m·yr or more compared with referent (<20 mg/m·yr). No consistent associations were observed between cumulative inhalable carbon black exposure and respiratory disease mortality. CONCLUSION: Quantitative carbon black exposure estimates were not related to lung cancer or nonmalignant respiratory disease mortality.

Formaldehyde Exposure and Mortality Risks From Acute Myeloid Leukemia and Other Lymphohematopoietic Malignancies in the US National Cancer Institute Cohort Study of Workers in Formaldehyde Industries.

OBJECTIVES: To evaluate associations between cumulative and peak formaldehyde exposure and mortality from acute myeloid leukemia (AML) and other lymphohematopoietic malignancies. METHODS: Cox proportional hazards analyses. RESULTS: Acute myeloid leukemia was unrelated to cumulative exposure. Hodgkin lymphoma relative risk estimates in the highest exposure categories of cumulative and peak exposures were, respectively, 3.76 (Ptrend = 0.05) and 5.13 (Ptrend = 0.003). There were suggestive associations with peak exposure observed for chronic myeloid leukemia, albeit based on very small numbers. No other lymphohematopoietic malignancy was associated with either chronic or peak exposure. CONCLUSIONS: Insofar as there is no prior epidemiologic evidence supporting associations between formaldehyde and either Hodgkin leukemia or chronic myeloid leukemia, any causal interpretations of the observed risk patterns are at most tentative. Findings from this re-analysis do not support the hypothesis that formaldehyde is a cause of AML.

A cohort mortality study of employees in the U.S. carbon black industry.

OBJECTIVES: The objectives of this study are to evaluate historical mortality patterns, especially due to cancers, among employees of the U.S. carbon black industry and to address the methodological shortcomings of previous U.S. mortality studies. METHODS: We followed mortality of 5011 workers employed 1 year or more since the 1930s at 18 carbon black facilities through December 31, 2003. Age-, race-, sex-, and calendar year-adjusted standardized mortality ratios (SMRs) were calculated using state-specific mortality rates. RESULTS: Follow up was 96% complete. All-cause (SMR = 0.74, 95% confidence interval [CI] = 0.70-0.78) and all-cancer mortality (SMR = 0.83, 95% CI = 0.74-0.92) showed significant deficits. No excess was observed from lung (SMR = 0.97, 95% CI = 0.82-1.15) or bladder (SMR = 0.93, 95% CI = 0.47-1.87) cancers or from nonmalignant respiratory diseases (SMR = 0.99, 95% CI = 0.83-1.18). No trends were seen with duration of employment or time since hire for any cause of death. CONCLUSION: Employment in carbon black production in the United States seems not to be associated with increased mortality overall, cancer overall and, in particular, lung cancer. Further research, however, incorporating a detailed exposure assessment is needed to determine whether exposure to carbon black at high levels may be associated with an increased risk of cancer.

Lung cancer mortality in the German chromate industry, 1958 to 1998.

OBJECTIVES: We conducted a mortality study of two German chromate production facilities and evaluated possible dose-response relationships between hexavalent chromium exposure and lung cancer. METHODS: Mortality was followed-up through 1998 and limited to those employed since each plant converted to a no-lime production process. More than 12,000 urinalysis results of chromium levels were available, as was smoking information. RESULTS: All-cause mortality indicated a healthy worker effect (standardized mortality ratio [SMR] = 0.80, 95% confidence interval [CI] = 0.67-0.96); however, lung cancers appeared to be increased (SMR = 1.48, 95% CI = 0.93-2.25). No clear dose-response was found in stratified analyses by duration of employment and time since hire. On the basis of urinary chromium data, lung cancer risk was elevated only in the highest exposure group (SMR = 2.09, 95% CI = 1.08-3.65). CONCLUSIONS: These data suggest a possible threshold effect of occupational hexavalent chromium exposure on lung cancer.

Low-level hexavalent chromium exposure and rate of mortality among US chromate production employees.

OBJECTIVE: Although numerous studies have reported an elevated lung cancer risk among chromium chemical production employees, few studies have focused on employees hired after major process changes and enhanced industrial hygiene controls were implemented. METHODS: This study examines the mortality experience of two post-change cohorts of chromate production employees constituting the current US chromium chemical industry. RESULTS: Mortality among chromium chemical workers generally was lower than expected on the basis of national and state-specific referent populations. Lung cancer mortality was 16% lower than expected, with only three lung cancer deaths (3.59 expected). CONCLUSION: The absence of an elevated lung cancer risk may be a favorable reflection of the post-change environment. However, longer follow-up allowing an appropriate latency for the entire cohort will be needed to confirm this conclusion.

Meta-analysis of studies of occupational exposure to vinyl chloride in relation to cancer mortality.

OBJECTIVE: A meta-analysis was made of studies addressing occupational exposure to vinyl chloride in relation to cancer mortality. METHODS: Two recently updated multicenter cohort studies and six smaller studies were identified. For selected neoplasms, standardized mortality ratios (SMR) and 95% confidence intervals (95% CI) were abstracted (or calculated from raw data). In cases of lack of heterogeneity (P-value > or = 0.01), meta-analyses were conducted using a random-effects model. RESULTS: With SMR values ranging from 1.63 to 57.1, all six studies for which these ratios could be obtained suggested an increased risk of liver cancer. For four of these studies, excesses persisted when known cases of angiosarcoma of the liver (ASL) were excluded. The meta-SMR for liver cancers other than ASL (based on the 2 large cohorts) was 1.35 (95% CI 1.04-1.77). The meta-SMR for lung cancer was 0.90 (95% CI 0.77-1.00, based on 5 studies), although higher SMR values were reported in early studies. The meta-SMR for brain cancer, based on 5 studies, was 1.26 (95% CI 0.98-1.62). For soft tissue sarcomas, the meta-SMR based on 4 studies was 2.52 (95% CI 1.56-4.07). The meta-SMR for lymphatic and hematopoietic neoplasms in the 2 large studies was 0.90 (95% CI 0.75-1.01), although 3 of the smaller studies reported significant excesses. CONCLUSIONS: Apart from the known risk of ASL, workers exposed to vinyl chloride may experience an increased risk of hepatocellular carcinoma and soft-tissue sarcoma; however, these results may have been influenced by the underdiagnosis of true ASL. Increased mortality from lung and brain cancers and from lymphatic and hematopoietic neoplasms cannot be excluded; mortality from other neoplasms does not appear to be increased.

Vinyl chloride and liver and brain cancer at a polymer production plant in Louisville, Kentucky.

Studies of overlapping cohorts in the United States have shown an excess mortality from brain cancer in vinyl chloride (VC)-exposed workers. One plant located in Louisville, Kentucky, is included in many of these studies. We separated this plant from the large US cohort and re-analyzed the mortality experience. Louisville experienced significantly elevated liver (standardized mortality analyses [SMR] = 400) and brain cancer (SMR = 229) mortality. Liver cancer mortality remained significantly elevated (SMR = 344) in the remaining cohort; however, brain cancer mortality was markedly reduced (SMR = 112) when Louisville was removed. In contrast with liver cancer, a preliminary review of work assignments did not suggest that the brain cancer excess was related to VC exposure. The Louisville brain cancer cluster has had a significant impact on the reported literature. Although unrelated to VC, the cause of this cluster remains uncertain.