Elongate mineral particles (EMP) characteristics and mesothelioma: Summary and resolution for session I of the Monticello II conference.

The summary contains a consensus opinion regarding the current state of the science about the dimensions of Elongate Mineral Particles (EMPs) as a factor impacting their carcinogenicity.

Risk of asbestosis, mesothelioma, other lung disease or death among motor vehicle mechanics: a 45-year Danish cohort study.

INTRODUCTION: The risk of asbestosis, malignant mesothelioma and lung cancer among motor vehicle mechanics is of concern because of potential exposure to chrysotile asbestos during brake, clutch and gasket repair and maintenance. Asbestos has also been used in insulation and exhaust systems. METHODS: We examined the long-term risk of incident mesothelioma, lung cancer, asbestosis and other lung diseases and mortality due to mesothelioma, lung cancer, asbestosis and other lung diseases in a nationwide cohort of all men registered as motor vehicle mechanics since 1970 in Denmark. This was compared with the corresponding risk in a cohort of male workers matched 10:1 by age and calendar year, with similar socioeconomic status (instrument makers, dairymen, upholsterers, glaziers, butchers, bakers, drivers, farmers and workers in the food industry, trade or public services). RESULTS: Our study included 138 559 motor vehicle mechanics (median age 24 years; median follow-up 20 years (maximum 45 years)) and 1 385 590 comparison workers (median age 25 years; median follow-up 19 years (maximum 45 years)). Compared with other workers, vehicle mechanics had a lower risk of morbidity due to mesothelioma/pleural cancer (n=47 cases) (age-adjusted and calendar-year-adjusted HR=0.74 (95% CI 0.55 to 0.99)), a slightly increased risk of lung cancer (HR=1.09 (95% CI 1.03 to 1.14)), increased risk of asbestosis (HR=1.50 (95% CI 1.10 to 2.03)) and a chronic obstructive pulmonary disease risk close to unity (HR=1.02 (95% CI 0.99 to 1.05)). Corresponding HRs for mortality were 0.86 (95% CI 0.64 to 1.15) for mesothelioma/pleural cancer, 1.06 (95% CI 1.01 to 1.12) for lung cancer, 1.79 (95% CI 1.10 to 2.92) for asbestosis, 1.06 (95% CI 0.86 to 1.30) for other lung diseases caused by external agents and 1.00 (95% CI 0.98 to 1.01) for death due to all causes. CONCLUSIONS: We found that the risk of asbestosis was increased among vehicle mechanics. The risk of malignant mesothelioma/pleural cancers was not increased among vehicle mechanics.

Measurement of asbestos emissions associated with demolition of abandoned residential dwellings.

Many cities are revitalizing their urban cores through the demolition of abandoned residential dwellings (ARDs). However, data regarding the emissions of asbestos during such an operation are sparse. We measured airborne asbestos emissions from emergency demolitions (demolitions on structures deemed too dangerous to enter and remove asbestos) of ARDs in Detroit. High-flow air sampling was conducted during ARD demolitions. Air samples were analyzed using Phased Contrast Microscopy (PCM), and a subset using Transmission Electron Microscopy (TEM). One hundred and one air samples were collected on 25 emergency demolitions. Fifty-four of the 101 PCM samples (53%) exceeded the limit of detection (LOD). However, only 2 of 46 TEM samples (4%) exceeded the LOD for asbestos; these latter samples were from two different demolitions and each contained a single chrysotile asbestos fiber. Using conservative exposure assumptions and commonly-accepted risk estimation formulae, we estimated the lifetime risk of mesothelioma and lung cancer combined to be less than one case per one million people. Emissions of airborne asbestos during emergency (unabated) ARD demolition operations appear to be negligible. As a result, the associated health risk for asbestos-related disease is also negligible. Reconsideration of current regulatory mandates for asbestos abatement in ARDs may be warranted.

A comparison of asbestos fiber potency and elongate mineral particle (EMP) potency for mesothelioma in humans.

We analyzed the mesothelioma mortality in cohorts of workers exposed to crocidolite, amosite, and chrysotile to estimate asbestos fiber potency for mesothelioma, using the method of Hodgson and Darnton (2000). We relied on the original 17 cohort studies in their analysis, along with 3 updates of those studies and 3 new asbestos cohort studies published since 2000. We extended the analyses to examine the mesothelioma potency of tremolite in vermiculite from Libby, Montana, and for non-asbestiform elongate mineral particles (EMPs) in taconite iron ore, talc, and South Dakota gold mining. Mesothelioma potency (RMeso) was calculated as the percent of all expected deaths that were due to mesothelioma per fiber/cc-year of exposure.The RMeso was 0.0012 for chrysotile, 0.099 for amosite, and 0.451 for crocidolite: thus, the relative potency of chrysotile:amosite:crocidolite was 1:83:376, which was not appreciably different from the estimates by Hodgson and Darnton in 2000. The RMeso for taconite mining fibers was 0.069 which was slightly smaller than that for amosite. The RMeso for Libby fibers was 0.028 which was greater than that for chrysotile and less than that for amosite. Talc and gold mining EMPs were non-potent for mesothelioma. Although there are a number of methods for estimating fiber potency of asbestos and non-asbestiform EMPs, the method of Hodgson and Darnton provides a uniform method by which fiber potency can be compared across many fiber types. Our estimates of RMeso provide a useful addition to our knowledge of mesothelioma potency for different asbestos and non-asbestiform EMP fibers.

Mesothelioma in the United States: a Surveillance, Epidemiology, and End Results (SEER)-Medicare investigation of treatment patterns and overall survival.

INTRODUCTION: Mesothelioma is a rare malignancy typically associated with exposure to asbestos and poor survival. The purpose of this investigation was to describe mesothelioma patient characteristics, treatment patterns, and overall survival (OS) utilizing the National Cancer Institute's Surveillance, Epidemiology, and End Results-Medicare database. MATERIALS AND METHODS: Patients in this study were diagnosed with malignant mesothelioma of the pleura or peritoneum between January 1, 2005 and December 31, 2009 with follow-up for survival through December 31, 2010. We examined both patient and tumor characteristics at time of diagnosis and subsequent treatment patterns (surgery, radiation, and chemotherapy). Among patients treated with chemotherapy, we determined chemotherapy regimen and OS by line of therapy. RESULTS: Of the 1,625 patients considered eligible for this investigation, the median age at diagnosis was 78 years. Nearly a third of patients (30%) had surgery as part of their treatment and 45% were given chemotherapy. The median OS was 8 months (range 1-69 months). Among chemotherapy patients, the most commonly (67%) prescribed regimen for first-line therapy was cisplatin or carboplatin (Ca/Ci) combined with pemetrexed (Pe). Among those prescribed Ca/Ci + Pe as first-line therapy, retreatment with Ca/Ci + Pe (28%) or treatment with gemcitabine (30%) were the most common second-line therapies. Median OS for those receiving first-line chemotherapy was 7 months, and among those receiving second-line therapy median OS was extended an additional 5 months. CONCLUSION: Irrespective of surgical resection, mesothelioma patients receiving some form of chemotherapy survived longer than patients who did not, with an additional survival benefit among those patients receiving multimodal treatment.

Mesothelioma among Motor Vehicle Mechanics: An Updated Review and Meta-analysis.

BACKGROUND: We published a meta-analysis of the association between work as a motor vehicle mechanic and mesothelioma in 2004. Since then, several relevant studies on this topic have been published. Thus, to update the state-of-the-science on this issue, we conducted a new systematic review and meta-analysis. METHODS: A comprehensive PubMed literature search through May 2014 was conducted to identify studies that reported relative risk estimates for mesothelioma among motor vehicle mechanics (in general), and those who were engaged in brake repair (specifically). Studies were scored and classified based on study characteristics. Random-effects meta-analyses generated summary relative risk estimates (SRREs) and corresponding 95% confidence intervals (CI). Heterogeneity of results was examined by calculating Q-test P-values (P-H) and I (2) estimates. Sub-group and sensitivity analyses were conducted for relevant study characteristics and quality measures. RESULTS: Ten case-control studies, one cohort study, and five proportionate mortality ratio (PMR)/standardized mortality odds ratio (SMOR) studies were identified and included in the quantitative assessment. Most meta-analysis models produced SRREs below 1.0, and no statistically significant increases in mesothelioma were observed. The SRRE for all studies was 0.80 (95% CI: 0.61-1.05) with significant heterogeneity (P-H <0.001, I (2) = 62.90). A similar SRRE was observed among the five Tier 1 studies with the highest quality ratings (SRRE = 0.76, 95% CI: 0.46-1.25), with no heterogeneity among studies (P-H = 0.912, I (2) = 0.00). Meta-analysis of the Tier 2 (n = 5) and Tier 3 (n = 6) studies resulted in SRREs of 1.09 (95% CI: 0.76-1.58) and 0.73 (95% CI: 0.49-1.08), respectively. Restricting the analysis to Tiers 1 and 2 combined resulted in an SRRE of 0.92 (95% CI: 0.72-1.29). The SRRE specific to brake work (n = 4) was 0.64 (95% CI: 0.38-1.09). CONCLUSIONS: This meta-analysis of the epidemiologic studies provides evidence that motor vehicle mechanics, including workers who were engaged in brake repair, are not at an increased risk of mesothelioma.

Historical cancer incidence and mortality assessment in an Illinois community proximal to a former manufactured gas plant.

OBJECTIVES: Concern has been raised that the occurrence of cancer may be increased in neighbourhoods around a former manufactured gas plant in Champaign, Illinois, USA. Thus, we compared historical rates of cancer in this area to comparison communities as well as with nationally standardised rates. DESIGN: Retrospective population-based community cancer assessment during 1990-2010. SETTING: Champaign County, Illinois, USA, and zip codes encompassing the location of the former manufactured gas plant to counties that were similar demographically. PARTICIPANTS: Residents of the counties and zip codes studied between 1990 and 2010. MAIN OUTCOME MEASURES: The relative risk (RR) and 95% CI were used to compare cancer incidence and mortality in the areas near the gas compression site to the comparison counties. Standardised incidence ratios (SIRs) were calculated to compare rates in the areas near the gas compression site to expected rates based on overall US cancer rates. RESULTS: Total cancer mortality (RR=0.91, 95% CI 0.88 to 0.94) and incidence (RR=0.95, 95% CI 0.94 to 0.97) were reduced significantly in Champaign County versus the comparison counties. Similarly, a reduced rate of total cancer was observed in analyses by zip code (proximal to the former gas plant) when compared with either similar counties (RR=0.89, 95% CI 0.86 to 0.93) or national standardised rates of cancer (SIR=0.88, 95% CI 0.85 to 0.91). CONCLUSIONS: This historical cancer assessment did not find an increased risk of total cancer or specific cancer types in communities near a former manufactured gas plant site.

A review and meta-analysis of cancer risks in relation to Portland cement exposure.

Workers engaged in the production of Portland cement may come into contact with potential occupational hazards, but existing epidemiological studies show wide variation in risk estimates for cancer incidence and mortality in relation to cement exposure. This report identified studies of cement workers and associations with cancer incidence and mortality in a systematic review and meta-analysis. A systematic review according to the PRISMA guidelines was conducted to identify studies of Portland cement workers and cancer outcomes. Meta-analyses were performed using random effects models for all cancers combined and for each cancer site with three or more reported measures of risk. A total of 26 studies were included in the review (14 occupational cohort studies and 12 case-control studies). Overall, the meta-relative risks did not provide convincing evidence for increased risks of any cancers in relation to cement exposure. Meta-SMR and 95% CIs were 0.94 (0.76 to 1.16) for six studies reporting all cancers combined, 0.93 (0.62 to 1.39) for seven studies reporting on lung cancer, 1.07 (0.72 to 1.59) for five studies reporting on stomach cancer, and 1.05 (0.79 to 1.40) for four studies reporting on colorectal cancer. Meta-relative risks for cancer incidence were similarly null for all sites with the exception of colorectal cancer which had a borderline statistically significant elevated risk (SIR=1.38, 95% CI 1.02 to 1.88). Overall, the meta-relative risks calculated across 26 published studies do not provide evidence of increased risks for cancer in relation to cement exposure.

Effects of occupational exposure to chlorpyrifos on neuropsychological function: a prospective longitudinal study.

BACKGROUND: Exposure to chlorpyrifos (CPF), an organophosphorus (OP) anticholinesterase insecticide, occurs typically in settings where multiple agents are present (e.g., agriculture) and quantitative dose measures may be absent (e.g., pesticide application). Such exposures allow few opportunities to study potential neurobehavioral effects of CPF alone. We studied the relationship between CPF exposure and behavioral function among CPF manufacturing workers, which allowed identification, measurement, and estimation of exposure and important non-exposure variables that potentially could affect study findings. METHODS: A prospective longitudinal study design was used to compare neurobehavioral function over a one-year period among 53 CPF workers and 60 referent workers. Quantitative and qualitative measures were used, and potential confounders were identified and tested for possible inclusion in our statistical models. Neurobehavioral function was assessed by neuropsychological tests covering various behavioral domains that may be adversely affected by exposure to CPF in sufficient amount. RESULTS: CPF workers had significantly greater CPF exposures during the study period than did referents at levels where physiologic effects on plasma butyrylcholinesterase (BuChE) activity were apparent and with higher 3,5,6-trichloro-2-pyridinol (TCPy/Cr) urinary excretion (p<0.0001) and lower average BuChE activity (p<0.01). No evidence for impaired neurobehavioral domains by either group of workers was observed at baseline, on repeat examination, or between examinations. CPF workers scored higher than referent workers on the verbal memory domain score (p=0.03) at baseline, but there were no significant changes in verbal memory over time and no significant group-by-time interactions. CONCLUSIONS: The study provides important information about CPF exposure in the workplace by not supporting our working hypothesis that CPF exposure associated with various aspects of the manufacturing process would be accompanied by adverse neurobehavioral effects detectable by quantitative neurobehavioral testing. Some aspects making this workplace site attractive for study and also present limitations for the generalization of results to other situations that might have exposures that vary widely between and within different facilities and locations. For example, these results might not apply to occupations such as applicators with higher exposure or to workers with low educational levels.

Childhood cancer incidence in Pennsylvania counties in relation to living in counties with hydraulic fracturing sites.

OBJECTIVE: Evaluate whether childhood cancer incidence is associated with counties with hydraulic fracturing (HF). METHODS: We compared cancer incidence in children in Pennsylvania counties before and after HF drilling began, using standardized incidence ratios (SIRs) and 95% confidence intervals (CIs). RESULTS: The total number of cancers observed was close to expected both before drilling began (SIR = 0.94; 95% CI, 0.90 to 0.99) and after drilling (SIR = 1.02; 95% CI, 0.98 to 1.07) for counties with oil and natural gas wells. Analyses for childhood leukemia were also unremarkable (SIR for leukemia before drilling = 0.97 [95% CI, 0.88 to 1.06]; SIR for leukemia after drilling = 1.01 [95% CI, 0.92 to 1.11]). A slightly elevated SIR was found for central nervous system tumors after drilling (SIR = 1.13; 95% CI, 1.02 to 1.25). This was because of a slight excess in those counties with the fewest number of wells. CONCLUSIONS: This study offers comfort concerning health effects of HF on childhood cancers.

The importance of problem formulations in risk assessment: a case study involving dioxin-contaminated soil.

The need to remediate contaminated soils is typically accomplished by applying standard risk assessment methods followed by risk management to select remedial options. These human health risk assessments (HHRAs) have been largely conducted in a formulaic manner that relies heavily on standard deterministic exposure, toxicity assumptions and fixed mathematical formulas. The HHRA approach, with its traditional formulaic practice, does not take advantage of problem formulation in the same manner as is done in ecological risk assessment, and historically, has generally failed to emphasize incorporation of site-specific information. In response to these challenges, the National Academy of Sciences recently made several recommendations regarding the conduct of HHRAs, one of which was to begin all such assessments with problem formulation. These recommendations have since been extended to dose response assessment. In accordance with these recommendations, a group of experts presented and discussed findings that highlighted the importance and impact of including problem formulation when determining the need for remediation of dioxin contamination in soils, focusing in particular on exposure assessment is described.

Estimation of age- and sex-specific background human serum concentrations of PCDDs, PCDFs, and PCBs in the UMDES and NHANES populations.

Age- and sex-specific estimates of serum dioxin concentrations are important for comparisons among populations. However, such comparisons are problematic because populations have different age and sex structures and values are typically reported only in broad age ranges that are not comparable across studies. There are few studies that report congener-specific serum concentrations, and none that provide these by sex for age as a continuous function. We combined the NHANES 2003-2004 data with the University of Michigan Dioxin Exposure Study (UMDES) referent population 2005 data to achieve stable and accurate estimates of mean and quantiles of serum dioxins by sex over ages 18-85. Survey-weighted linear and quantile regression models were fitted on the combined data with the log-transformed congener concentration as outcome and age, sex, and data source as covariates. Formulas are provided to allow calculations of age- and sex-specific mean and quantile estimates over ages 18-85. For instance, the geometric mean, median, 75th percentile, and 95th percentile of serum TEQ for men aged 50 can be estimated, respectively, from the formulas as 18.33, 19.02, 22.60, and 30.37 pg g(-1) lipids among the Michigan general population, and as 15.71, 15.89, 22.60, and 29.90 pg g(-1) lipids among US non-Hispanic whites. These methods and results are useful for comparing the congener-specific human serum dioxin concentrations in any individual to the general population mean, median, 75th percentile, and 95th percentile, and for comparing the serum dioxin concentration in any group of interest to the US and the Michigan general populations.

Polytopic vector analysis of soil, dust, and serum samples to evaluate exposure sources of PCDD/Fs.

As part of the University of Michigan Dioxin Exposure Study, soil, household dust, and serum samples were collected from more than 750 households in five populations around the city of Midland and in Jackson and Calhoun Counties, Michigan, USA. Polytopic vector analysis, a type of receptor model, was applied to better understand the potential sources of polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans found in these samples and to quantify the contributions of the sources in each matrix across populations. The results indicated that source signatures found in soil are similar to those found in dust, reflecting various combustion profiles, pentachlorophenol, and graphite electrode sludge. The profiles associated with contamination in the Tittabawassee River, likely related to historical discharges from the Dow Chemical Company facility in Midland, exhibited the largest differences among the regional populations sampled. Differences in serum source contributions among the study populations were consistent with some of the regional differences observed in soil samples. However, the age trends of these differences suggested that they are related to past exposures, rather than ongoing sources.

Hierarchical cluster analysis of polychlorinated dioxins and furans in Michigan, USA, soils: evaluation of industrial and background congener profiles.

As part of the University of Michigan Dioxin Exposure Study, soil samples were collected from 766 residential properties near the Tittabawassee River between Midland and Saginaw; near the Dow Chemical Facility in Midland; and, for comparison, in the other areas of Midland and Saginaw Counties and in Jackson and Calhoun Counties, all located in the state of Michigan, USA. A total of 2,081 soil samples were analyzed for 17 polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs). In order to better understand the distribution and sources of the PCDD/F congeners in the study area, hierarchical cluster analysis (HCA) was used to statistically group samples with similar congener patterns. The analysis yielded a total of 13 clusters, including: 3 clusters among the soils impacted by contamination present in the Tittabawassee River sediments, a cluster comprised mainly of samples collected within the depositional area of the Dow incinerator complex, a small cluster of samples with elevated 2,3,7,8-tetrachlorinated dibenzo-p-dioxin (TCDD), and several clusters exhibiting background patterns. The clusters related to the Tittabawassee River floodplain contamination all contained elevated PCDF levels and were differentiated from one another primarily by their relative concentrations of higher-chlorinated PCDDs, a difference likely related to both extent and timing of impacts from Tittabawassee sediments. The background clusters appear to be related to combustion processes and are differentiated, in part, by their relative fractions of TCDD. Thus, HCA was useful for identifying congener profile characteristics in both contaminated and background soil samples.

Case report: the University of Michigan dioxin exposure study: a follow-up investigation of a case with high serum concentration of 2,3,4,7,8-pentachlorodibenzofuran.

CONTEXT: Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and dioxin-like polychlorinated biphenyls that have toxic equivalency factors (TEFs) were measured in serum of 946 subjects in five Michigan counties. The study was motivated by concerns about human exposure to dioxin-contaminated sediments in the Tittabawassee River (TR). Most of the toxic equivalency in TR sediments is from two furan congeners, 2,3,7,8-tetrachlorodibenzofuran and 2,3,4,7,8-pentachlorodibenzofuran (2,3,4,7,8-pentaCDF). CASE PRESENTATION: The individual with the highest adjusted (for age, age squared, and body mass index) serum level of 2,3,4,7,8-pentaCDF in the study (42.5 ppt) reported a unique history of raising cattle and vegetables in the floodplain of the TR. Interviews and serum samples were obtained from the index case and 15 other people who ate beef and vegetables raised by the index case. 2,3,4,7,8-pentaCDF in beef lipid was estimated to have been more than three orders of magnitude greater than background (1,780 vs. 1.1 ppt). The mean, median, and 95th percentile for serum 2,3,4,7,8-pentaCDF in the study control population were 6.0, 5.4, and 13.0 ppt, respectively, and were 9.9, 8.4, and 20.5 ppt among beef and vegetable consumers, respectively. Back extrapolation for the index case suggests that his increase in serum concentration of 2,3,4,7,8-pentaCDF above background may have been as high as 146 ppt. DISCUSSION: Consumption of beef and/or vegetables raised on dioxin-contaminated soil may be an important completed pathway of exposure. RELEVANCE TO PUBLIC HEALTH PRACTICE: Animals and crops should not be raised for human consumption in areas contaminated with dioxins.

Estimating population distributions when some data are below a limit of detection by using a reverse Kaplan-Meier estimator.

BACKGROUND: Data with some values below a limit of detection (LOD) can be analyzed using methods of survival analysis for left-censored data. The reverse Kaplan-Meier (KM) estimator provides an effective method for estimating the distribution function and thus population percentiles for such data. Although developed in the 1970s and strongly advocated since then, it remains rarely used, partly due to limited software availability. METHODS: In this paper, the reverse KM estimator is described and is illustrated using serum dioxin data from the University of Michigan Dioxin Exposure Study (UMDES) and the National Health and Nutrition Examination Survey (NHANES). Percentile estimates for left-censored data using the reverse KM estimator are compared with replacing values below the LOD with the LOD/2 or LOD/ radical2. RESULTS: When some LODs are in the upper range of the complete values, and/or the percent censored is high, the different methods can yield quite different percentile estimates. The reverse KM estimator, which is the nonparametric maximum likelihood estimator, is the preferred method. Software options are discussed: The reverse KM can be calculated using software for the KM estimator. The JMP and SAS (SAS Institute, Cary, NC) and Minitab (Minitab, Inc, State College, PA), software packages calculate the reverse KM directly using their Turnbull estimator routines. CONCLUSION: The reverse KM estimator is recommended for estimation of the distribution function and population percentiles in preference to commonly used methods such as substituting LOD/2 or LOD/ radical2 for values below the LOD, assuming a known parametric distribution, or using imputation to replace the left-censored values.

Estimation of background serum 2,3,7,8-TCDD concentrations by using quantile regression in the UMDES and NHANES populations.

BACKGROUND: The goal of the present study was to quantify the population-based background serum concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) by using data from the reference population of the 2005 University of Michigan Dioxin Exposure Study (UMDES) and the 2003-2004 National Health and Nutrition Examination Survey (NHANES). METHODS: Multiple imputation was used to impute the serum TCDD concentrations below the limit of detection by combining the 2 data sources. The background mean, quartiles, and 95th percentile serum TCDD concentrations were estimated by age and sex by using linear and quantile regressions for complex survey data. RESULTS: Any age- and sex-specific mean, quartiles, and 95th percentiles of background serum TCDD concentrations of study participants between ages 18 and 85 years can be estimated from the regressions for the UMDES reference population and the NHANES non-Hispanic white population. For example, for a 50-year-old man in the reference population of UMDES, the mean, quartiles, and 95th percentile serum TCDD concentrations are estimated to be 1.1, 0.6, 1.1, 1.8, and 3.3 parts per trillion, respectively. The study also shows that the UMDES reference population is a valid reference population for serum TCDD concentrations for other predominantly white populations in Michigan. CONCLUSION: The serum TCDD concentrations increased with age and increased more over age in women than in men, and hence estimation of background concentrations must be adjusted for age and sex. The methods and results discussed in this article have wide application in studies of the concentrations of chemicals in human serum and in environmental samples.

Paraoxonase status and plasma butyrylcholinesterase activity in chlorpyrifos manufacturing workers.

Chlorpyrifos is an organophosphorus (OP) anticholinesterase insecticide. Paraoxonase (PON1) is an enzyme found in liver and plasma that hydrolyzes a number of OP compounds. PON1 polymorphisms include a glutamine (Q)/arginine (R) substitution at position 192 (PON1(Q192R)) that affects hydrolysis of OP substrates, with the PON1(192Q) allotype hydrolyzing chlorpyrifos oxon less efficiently than the PON1(192R) allotype, a variation potentially important in determining susceptibility to chlorpyrifos. We studied 53 chlorpyrifos workers and 60 referents during 1 year and estimated chlorpyrifos exposure using industrial hygiene and employment records and excretion of the chlorpyrifos metabolite 3,5,6-trichloro-2-pyridinol (TCP). Plasma butyrylcholinesterase (BuChE) activity, which may by inhibited by chlorpyrifos exposure, was measured monthly. In addition, plasma samples were assayed for paraoxonase (PONase), diazoxonase (DZOase), and chlorpyrifosoxonase (CPOase) activity to determine PON1 status (inferred genotypes and their functional activity). Linear regression analyses modeled BuChE activity as a function of chlorpyrifos exposure and covariates. We postulated that the level of CPOase activity and the inferred PON1(192) genotype (together reflecting PON1 status) would differ between groups and that PON1 status would modify the models of chlorpyrifos exposure on BuChE activity. Chlorpyrifos workers and referents had a 100-fold difference in cumulative chlorpyrifos exposure. Contrary to our hypotheses, mean CPOase activity was similar in both groups (P=0.58) and PON1(192Q) showed a slight overrepresentation, not an underrepresentation, in the chlorpyrifos group compared with referents (PON1(192QQ), 51% chlorpyrifos, 40% referent; PON(192QR), 43% chlorpyrifos, 40% referent; PON(192RR), 6% chlorpyrifos, 20% referent, P=0.08). In our models, BuChE activity was significantly inversely associated with measures of interim chlorpyrifos exposure, but the biological effects of chlorpyrifos exposure on BuChE activity were not modified by PON1 inferred genotype or CPOase activity.