Cancer risk among tetrafluoroethylene synthesis and polymerization workers.

Tetrafluoroethylene (TFE), a compound used for the production of fluorinated polymers including polytetrafluoroethylene, increases the incidence of liver and kidney cancers and leukemia in rats and mice. This is the first time the cancer risk in humans has been explored comprehensively in a cohort mortality study (1950-2008) that included all polytetrafluoroethylene production sites in Europe and North America at the time it was initiated. A job-exposure matrix (1950-2002) was developed for TFE and ammonium perfluoro-octanoate, a chemical used in the polymerization process. National reference rates were used to calculate standardized mortality ratios (SMRs) and 95% confidence intervals. Among 4,773 workers ever exposed to TFE, we found a lower rate of death from most causes, as well as increased risks for cancer of the liver (SMR = 1.27; 95% confidence interval: 0.55, 2.51; 8 deaths) and kidney (SMR = 1.44; 95% confidence interval: 0.69, 2.65; 10 deaths) and for leukemia (SMR = 1.48; 95% confidence interval: 0.77, 2.59; 12 deaths). A nonsignificant upward trend (P = 0.24) by cumulative exposure to TFE was observed for liver cancer. TFE and ammonium perfluoro-octanoate exposures were highly correlated, and therefore their separate effects could not be disentangled. This pattern of findings narrows the range of uncertainty on potential TFE carcinogenicity but cannot conclusively confirm or refute the hypothesis that TFE is carcinogenic to humans.

A systematic approach for evaluating and scoring human data.

An approach is described for how the quality of human data can be systematically assessed and categorised. The approach mirrors the animal data quality considerations set out by Klimisch et al., in order that human data quality can be addressed in a complementary manner and to help facilitate transparent (and repeatable) weight of evidence comparisons. Definitions are proposed for the quality and adequacy of data. Quality is differentiated into four categories. A description of how the scheme can be used for evaluating data reliability, especially for use when contributing entries to the IUCLID database, is shown. A discussion of how the criteria might also be used when determining overall data relevance is included. The approach is intended to help harmonise human data evaluation processes worldwide.

Dose ingested, vomiting, and outcome in patients ingesting a standard paraquat 20SL formulation.

BACKGROUND: FAO specifications for liquid paraquat dichloride SL formulations require the use of an emetic agent to stimulate vomiting within 30 min of ingestion. To date, there is no high-quality evidence of efficacy, despite use of the PP796 emetic since 1979. We first examined the validity of patients' self-reported dose of paraquat ingested by examining the relationship with blood paraquat concentration and time to death for patients ingesting the standard paraquat SL formulation in a Sri Lankan cohort. As a secondary outcome, we assessed whether ingestion resulted in vomiting within 30 min and whether vomiting was associated with good outcome. METHODS: Patients presenting with paraquat SL self-poisoning were prospectively studied in ten Sri Lankan hospitals in 2003-08. Data on reported dose ingested, incidence and timing of vomiting after ingestion, treatment received, plasma paraquat concentration, and outcome were collected prospectively on presentation to hospital. Time between ingestion and blood sampling was incorporated by covariate adjustment. RESULTS: 441 patients were recruited to the case series, presenting a median (IQR) of 3.0 (1.5-8.1] h post ingestion. Outcome was known for 435 patients of whom 322 (74.0%) died within 42 days, a median of 1.3 (0.6-4.4) days post ingestion. Median reported dose ingested was 15 to <30 mL. There was a highly significant linear trend between log plasma paraquat and reported dose ingested (p < .001); adjustment for the log of the time from ingestion to sampling further improved the model fit. Case fatality and median time to death also showed good agreement with estimated ingestion amount. 347/438 patients (79.2%) were stated to have vomited before reaching the study hospital with 300 (68.5%) vomiting within 30 min of ingestion; time to vomiting was unknown for a further 12 (2.7%). The proportion vomiting was strongly associated with reported dose ingested (p < .001); of note the proportion vomiting within 30 min only increased to 83.3% for the highest ingestion group. Patients vomiting within 30 min had higher plasma paraquat concentrations (p = .008), and higher hazard ratio in the adjusted Cox regression model of 2.01 (95% CI 1.45-2.77) compared to those who did not. Vomiting within 30 min was associated with a higher case fatality (241/295 [81.7%] vs 68/125 [54.4%], p < .001). Forty-three (47.3%) of the 91 patients who did not vomit before reaching hospital died (one had unknown outcome). CONCLUSION: Importantly, we found good agreement between reported dose ingested and plasma paraquat concentration, case fatality, and time to death, suggesting that the reported dose is a valid marker for the dose ingested. Vomiting occurred within 30 min for 68.5% of patients, exceeding the characteristics for a purported effective emetic in the FAO specifications. However, vomiting within 30 min was associated with approximately double the risk of death compared to those who did not vomit, larger paraquat ingestions, and higher blood paraquat concentrations. In addition, death occurred in many patients who did not vomit, and the proportion vomiting within 30 min only reached 82.1% for the highest ingested dose group. Overall, we found no evidence of benefit resulting from incorporation of the emetic, suggesting that the current FAO specification is not effective at preventing deaths after ingestion of the paraquat SL formulation.

Update of a cohort mortality study of workers exposed to methylene chloride employed at a plant producing cellulose triacetate film base.

PURPOSE: To update the mortality experience of employees of a factory that produced cellulose triacetate film base at Brantham in the United Kingdom and generate information on the effects of exposure to methylene chloride, in particular, mortality from cardiovascular disease and cancers of the lung, liver and biliary tract, pancreas and brain. METHODS: All 1,785 male employees with a record of employment at the film factory in 1946-1988 were followed through 2006, including 1,473 subjects exposed to methylene chloride on average for 9 years at a concentration of 19 ppm (8 h time-weighted average). RESULTS: A total of 559 deaths occurred during the follow-up period. In the subcohort of workers exposed to methylene chloride, substantially reduced mortalities compared with national and local rates were found for all causes, all cancers, and all the principal cancer sites of interest except for brain cancer. There was a small excess of brain cancer deaths (8 observed and 4.4 expected), but no evidence of an association with exposure to methylene chloride. Lung cancer mortality was significantly reduced in exposed workers, even compared to the low mortality rate in the local population (SMR 55). In contrast, mortality from ischaemic heart disease in exposed workers was slightly increased compared with local rates (SMR 102), but was lower in active employees (SMR 94; local rates), where a direct effect of exposure to methylene chloride should be concentrated. CONCLUSIONS: The study provided no indication that employment at the plant, or exposure to methylene chloride, had adversely affected the mortalities of workers.

Mortality from Parkinson's disease and other causes among a workforce manufacturing paraquat: an updated retrospective cohort study.

BACKGROUND: Epidemiological studies of the association between Parkinson's disease (PD) and paraquat (PQ) exposure have given inconsistent findings. The aim of the study was to update information on the risk of PD and mortality from major causes of death among a UK workforce who manufactured PQ by extending the follow-up by seven and a half years. METHODS: This retrospective cohort study included all employees who had ever worked on any of the four plants at Widnes, UK where PQ was manufactured between 1961 and 1995. The 926 male and 42 female workers were followed through 31 December 2017. Mortalities for males were compared with national and local rates, including rates for PD as a mentioned cause of death. RESULTS: A total of 394 male and 21 female workers had died by end of follow-up. Four death certificates of male workers mentioned PD, including two deaths that were due to PD. At least 6 death certificates of male employees would have been expected to have mentioned PD (SMR = 0.67; 95% CI 0.18-1.72). Reduced mortalities compared with local rates were found for major causes of death. CONCLUSIONS: The study provided no evidence of an increased risk of PD, or increased mortalities from other causes among PQ production workers whose exposure to PQ on a daily basis was at least comparable to that of a PQ sprayer or mixer/loader.

Causes and types of health effects during the use of crop protection chemicals: data from a survey of over 6,300 smallholder applicators in 24 different countries.

PURPOSE: The present investigation looks in detail at the causes and types of health incidents reported by 6,300 mainly smallholder agrochemical users in 24 countries during 2005 and 2006. METHODS: The investigation is based on a questionnaire survey of knowledge, attitude and practice that concentrated on the sequence of events from purchasing the pesticide to disposal. Information was also collected about health problems experienced while using agrochemicals. The survey targeted mainly smallholder knapsack spray operators who were expected to be at a highest risk of exposure. RESULTS: In the 12 months prior to interview, 1.2% of users reported an agrochemical-related incident that required hospital treatment, 5.8% reported an incident requiring at least trained medical treatment but not hospitalisation and 19.8% reported only a minor sign or symptom. Users who had experienced an incident involving agricultural equipment were 3.38 (95% CI 2.29-4.99) times more likely to experience an agrochemical-related health incident, but confident users who felt that their use of personal protective equipment while spraying was best practice were 0.60 (95% CI 0.44-0.84) times less likely to experience such an incident. Over 80% of product-related incidents were caused by insecticides and the incidence rate per spraying time for incidents linked to insecticides was significantly higher than that for fungicides or herbicides. Headache/dizziness and nausea/vomiting, often smell related, were the most common symptoms reported by users who listed agrochemical products that had caused them health problems (52 and 38% of product mentions, respectively). CONCLUSIONS: In most countries, the incidence of serious health effects was low; however, there was a high incidence of minor signs and symptoms in a few countries, especially in Africa. A disproportionate number of incidents occurred during insecticide use relative to the time that they were sprayed. Failure to exercise caution as indicated by whether users had incidents involving agricultural equipment or livestock, and lack of confidence in their practices were the most important predictors of agrochemical-related incidents.

Improvement in survival after paraquat ingestion following introduction of a new formulation in Sri Lanka.

BACKGROUND: Pesticide ingestion is a common method of self-harm in the rural developing world. In an attempt to reduce the high case fatality seen with the herbicide paraquat, a novel formulation (INTEON) has been developed containing an increased emetic concentration, a purgative, and an alginate that forms a gel under the acid conditions of the stomach, potentially slowing the absorption of paraquat and giving the emetic more time to be effective. We compared the outcome of paraquat self-poisoning with the standard formulation against the new INTEON formulation following its introduction into Sri Lanka. METHODS AND FINDINGS: Clinical data were prospectively collected on 586 patients with paraquat ingestion presenting to nine large hospitals across Sri Lanka with survival to 3 mo as the primary outcome. The identity of the formulation ingested after October 2004 was confirmed by assay of blood or urine samples for a marker compound present in INTEON. The proportion of known survivors increased from 76/297 with the standard formulation to 103/289 with INTEON ingestion, and estimated 3-mo survival improved from 27.1% to 36.7% (difference 9.5%; 95% confidence interval [CI] 2.0%-17.1%; p = 0.002, log rank test). Cox proportional hazards regression analyses showed an approximately 2-fold reduction in toxicity for INTEON compared to standard formulation. A higher proportion of patients ingesting INTEON vomited within 15 min (38% with the original formulation to 55% with INTEON, p < 0.001). Median survival time increased from 2.3 d (95% CI 1.2-3.4 d) with the standard formulation to 6.9 d (95% CI 3.3-10.7 d) with INTEON ingestion (p = 0.002, log rank test); however, in patients who did not survive there was a comparatively smaller increase in median time to death from 0.9 d (interquartile range [IQR] 0.5-3.4) to 1.5 d (IQR 0.5-5.5); p = 0.02. CONCLUSIONS: The survey has shown that INTEON technology significantly reduces the mortality of patients following paraquat ingestion and increases survival time, most likely by reducing absorption.

A Review and Meta-Analysis of Occupational Titanium Dioxide Exposure and Lung Cancer Mortality.

OBJECTIVE: A review of studies of occupational titanium dioxide (TiO2) exposure was conducted, and results from the three industry-based cohort mortality studies were summarized using meta-analysis. METHODS: Summary standardized mortality ratios (SSMR) and summary Cox regression coefficients from exposure-response models were derived using random effects models. RESULTS: Results from studies of 24,312 TiO2 production workers were combined. SSMRs for lung cancer, all causes, all cancer, and non-malignant respiratory disease were 1.10 (95% confidence interval [CI]: 0.91 to 1.32), 0.85 (95% CI: 0.81 to 0.89), 0.92 (95% CI: 0.82 to 1.03), and 0.85 (95% CI: 0.71 to 1.02), respectively. For lung cancer, the summary hazard ratio for a 1 mg/m year increase in cumulative exposure was 0.999 (0.997 to 1.002). CONCLUSIONS: Consistent with other published qualitative reviews, there is no clear evidence of an association between occupational exposure to TiO2 and lung cancer.

High-dose immunosuppression to prevent death after paraquat self-poisoning - a randomised controlled trial.

CONTEXT: Intentional self-poisoning with the herbicide paraquat has a very high case-fatality and is a major problem in rural Asia and Pacific. OBJECTIVES: We aimed to determine whether the addition of immunosuppression to supportive care offers benefit in resource poor Asian district hospitals. MATERIALS AND METHODS: We performed a randomised placebo-controlled trial comparing immunosuppression (intravenous cyclophosphamide up to 1 g/day for two days and methylprednisolone 1 g/day for three days, and then oral dexamethasone 8 mg three-times-a-day for 14 days) with saline and placebo tablets, in addition to standard care, in patients with acute paraquat self-poisoning admitted to six Sri Lankan hospitals between 1st March 2007 and 15th November 2010. The primary outcome was in-hospital mortality. RESULTS: 299 patients were randomised to receive immunosuppression (147) or saline/placebo (152). There was no significant difference in in-hospital mortality rates between the groups (immunosuppression 78 [53%] vs. placebo 94 [62%] (Chi squared test 2.4, p = .12). There was no difference in mortality at three months between the immunosuppression (101/147 [69%]) and placebo groups (108/152 [71%]); (mortality reduction 2%, 95% CI: -8 to +12%). A Cox model did not support benefit from high-dose immunosuppression but suggested potential benefit from the subsequent two weeks of dexamethasone. CONCLUSIONS: We found no evidence that high dose immunosuppression improves survival in paraquat-poisoned patients. The continuing high mortality means further research on the use of dexamethasone and other potential treatments is urgently needed.

Epidemiologic studies of occupational pesticide exposure and cancer: regulatory risk assessments and biologic plausibility.

Epidemiologic studies frequently show associations between self-reported use of specific pesticides and human cancers. These findings have engendered debate largely on methodologic grounds. However, biologic plausibility is a more fundamental issue that has received only superficial attention. The purpose of this commentary is to review briefly the toxicology and exposure data that are developed as part of the pesticide regulatory process and to discuss the applicability of this data to epidemiologic research. The authors also provide a generic example of how worker pesticide exposures might be estimated and compared to relevant toxicologic dose levels. This example provides guidance for better characterization of exposure and for consideration of biologic plausibility in epidemiologic studies of pesticides.

Mortality from Parkinson's disease and other causes among a workforce manufacturing paraquat: a retrospective cohort study.

Objective To assess the risk of Parkinson's disease (PD) and update information on mortality from major causes of death among a UK workforce who manufactured paraquat (PQ) between 1961 and 1995. There have been no previous studies of the incidence of PD among PQ production workers, although much epidemiological literature exists concerning the relationship between pesticides and PD, and interest has focused on PQ and its users. Methods The cohort included all employees who had ever worked on any of the four plants at Widnes where PQ was manufactured between 1961 and 1995, and 926 male and 42 female workers were followed through 30 June 2009. Mortalities for males were compared with national and local rates, including rates for PD as a mentioned cause of death. Results Overall, 307 workers had died by 30 June 2009. One male death was due to PD, and no other death certificate mentioned PD. At least 3.3 death certificates of male employees would have been expected to have mentioned PD (standardised mortality ratio=31; 95% CI 1 to 171). Personal monitoring results were indicative that the exposure of a PQ production worker on a daily basis was at least comparable with that of a PQ sprayer or mixer/loader. Reduced mortalities compared with local rates were found for major causes of death. Conclusions The study provided no evidence of an increased risk of PD, or increased mortalities from other causes.

Formulation changes and time trends in outcome following paraquat ingestion in Sri Lanka.

INTRODUCTION: Deliberate self-harm with pesticides is a significant public health problem in rural Asia. We have previously shown an improved survival of patients with paraquat self-poisoning following the introduction of a new formulation with an increased emetic concentration, an alginate and a purgative in Sri Lanka. Further, formulation changes were introduced in October 2006; this study was designed to assess the impact of these changes on 6-week mortality following paraquat ingestion. METHODS: Prospective, cohort study of patients admitted with paraquat poisoning to 10 hospitals across Sri Lanka between September 2006 and September 2008. RESULTS: Overall, there was a significant (p < 0.001) increase in survival in the 533 patients included in this study compared to previous data (44.5 vs. 35.2% before September 2006 and 27.1% before October 2004). Patients ingesting the new INTEON formulation had a higher survival rate than those ingesting standard formulation (40.2 vs. 31.0%), but this effect was not statistically significant in Cox's proportional hazards model (hazard ratio 0.81, 95% CI 0.61?1.08 (unadjusted) and 1.17, 95% CI 0.82?1.68 (fully adjusted), respectively). CONCLUSIONS: This study has confirmed a continued improvement in survival of patients following self-harm with paraquat in Sri Lanka in recent years; however, in contrast to previous investigations, a beneficial effect associated with the INTEON formulation could not be substantiated. This may be partly due to the large number of patients in whom paraquat concentrations were too low for analytical confirmation of the formulation (n = 105) and who had a very high survival rate (86.7%).

Critical review of the epidemiology literature on the potential cancer risks of methyl methacrylate.

OBJECTIVE: To critically review and summarise all of the available epidemiological evidence, both published and unpublished, to date on the carcinogenicity of methyl methacrylate (MMA) to humans. METHODS: The review focused on studies of cast acrylic sheet manufacturing workers because this industry has historically had a potential for exposure to high levels of MMA. The majority of papers for review were identified through Medline (National Library of Medicine) but there is some discussion of two cohort studies and a nested case-control study, which to date have not been published. RESULTS: An increased risk of colorectal cancer was reported in one group of workers highly exposed to MMA and ethyl acrylate (EA) in the manufacture of acrylic sheet. Analysis of colon cancer by cumulative exposure to MMA indicated that the excess was largely confined to the group with the highest exposure. However, a large excess of colon cancer deaths occurred among workers who never worked in a job entailing more than minimal exposure. Studies of other large occupational cohorts of workers potentially exposed to MMA, including some with potentially comparable exposures, have failed to strengthen the evidence that there is a causal association between colorectal cancer and MMA exposure although one reported an excess that did not appear to be exposure-related. Excesses of cancers of the respiratory system and stomach were seen in some cohorts, but not among the acrylic sheet workers who had the increased risk of colorectal cancer. CONCLUSIONS: Excesses of respiratory, stomach and colorectal cancers were observed in some cohorts of workers exposed to MMA. There was little to suggest that MMA exposure was responsible for the excesses of respiratory and stomach cancer and it is more likely that they resulted from unexplained contributions of lifestyle exposures such as cigarette smoking and diet. An excess of colorectal cancer in one group of workers exposed to high levels of MMA and EA during the 1930s and 1940s remains unexplained. However, the lack of consistency in the results of various studies, the absence of dose response and the lack of support from animal toxicology do not provide persuasive evidence that exposure to MMA is a human carcinogen.

Titanium dioxide: inhalation toxicology and epidemiology.

Titanium dioxide (TiO(2)) is manufactured worldwide in large quantities for use in a wide range of applications and is normally considered to be toxicologically inert. Findings of tumours in the lungs of rats exposed chronically to high concentrations of TiO(2), but not in similarly exposed mice or hamsters, suggest that the tumorigenic response may be a rat-specific phenomenon but nonetheless raises concerns for potential human health effects. With the limited toxicological understanding of species differences in response to inhaled TiO(2) and a similarly limited amount of epidemiological information with respect to TiO(2) exposure in the workplace, a consortium of TiO(2) manufacturers in Europe (under the European Chemistry Industry Council; CEFIC) and in North America (under the American Chemistry Council; ACC) initiated a programme of research to investigate inter-species differences as a result of exposure to TiO(2) and to conduct detailed epidemiological surveys of the major manufacturing sites. The toxicology studies exposed rats, mice and hamsters to pigment-grade TiO(2) (PG-TiO(2), 0, 10, 50 and 250 mg m(-3)) or ultrafine TiO(2) (UF-TiO(2), 0, 0.5, 2 and 10 mg m(-3)) for 90 days and the lung burdens and tissue responses were evaluated at the end of the exposure period and for up to 1 year after exposure. Results demonstrated clear species differences. Rats and mice had similar lung burdens and clearance rates while hamsters showed high clearance rates. At high lung particle burdens, rats showed a marked progression of histopathological lesions throughout the post-exposure period while mice and hamsters showed minimal initial lesions with recovery apparent during the post-exposure period. Lung neutrophil responses, a sensitive marker of inflammatory changes, reflected the development or recovery of the histopathological lesions. The use of surface area rather than gravimetric lung burden provided closer correlates of the burden to the biological effect across both TiO(2) types. The epidemiological investigations evaluated the mortality statistics at 11 European and 4 US TiO(2) manufacturing plants. They concluded that there was no suggestion of any carcinogenic effect associated with workplace exposure to TiO(2).