Bisphenol A is a commercially important chemical used to make polycarbonate plastic, epoxy resins and other specialty products. Despite an extensive body of in vitro, animal and human observational studies on the effects of exposure to bisphenol A, no authoritative bodies in the U.S. have adopted or recommended occupational exposure limits for bisphenol A. In 2017, the National Institute for Occupational Safety and Health published a Draft process for assigning health-protective occupational exposure bands, i.e. an airborne concentration range, to chemicals lacking an occupational exposure limit. Occupational exposure banding is a systematic process that uses both quantitative and qualitative toxicity information on selected health effect endpoints to assign an occupational exposure band for a chemical. The Draft process proposes three methodological tiers of increasing complexity for assigning an occupational exposure band. We applied Tier 1 (based on the Globally Harmonized System of Classification and Labelling) and Tier 2 (based on authoritative sources/reviews) to assign an occupational exposure band to bisphenol A. Under both Tier 1 and 2, the occupational exposure band for bisphenol A was "E" (<0.01 mg/m(3)), an assignment based on eye damage. "E" is the lowest exposure concentration range, reserved for chemicals with high potential toxicity. If eye damage was excluded in assigning an air concentration exposure range, then bisphenol A would band as "D" (>0.01 to 0.1 mg/m(3)) under Tier 1 (based on reproductive toxicity and respiratory/skin sensitization) and under Tier 2 (based on specific target organ toxicity-repeated exposure). In summary, Tiers 1 and 2 gave the same occupational exposure band for bisphenol A when eye damage was included ("E") or excluded ("D") as an endpoint.

Residents of agricultural areas experience pesticide exposures from sources other than direct agricultural work. We developed a quantitative, active ingredient-specific algorithm for cumulative (adult, married lifetime) non-occupational pesticide exposure intensity for spouses of farmers who applied pesticides in the Agricultural Health Study (AHS). The algorithm addressed three exposure pathways: take-home, agricultural drift, and residential pesticide use. Pathway-specific equations combined (i) weights derived from previous meta-analyses of published pesticide exposure data and (ii) information from the questionnaire on frequency and duration of pesticide use by applicators, home proximity to treated fields, residential pesticide usage (e.g., termite treatments), and spouse's off-farm employment (proxy for time at home). The residential use equation also incorporated a published probability matrix that documented the likelihood active ingredients were used in home pest treatment products. We illustrate use of these equations by calculating exposure intensities for the insecticide chlorpyrifos and herbicide atrazine for 19,959 spouses. Non-zero estimates for >/=1 pathway were found for 78% and 77% of spouses for chlorpyrifos and atrazine, respectively. Variability in exposed spouses' intensity estimates was observed for both pesticides, with 75th to 25th percentile ratios ranging from 7.1 to 7.3 for take-home, 6.5 to 8.5 for drift, 2.4 to 2.8 for residential use, and 3.8 to 7.0 for the summed pathways. Take-home and drift estimates were highly correlated (>/=0.98), but were not correlated with residential use (0.010.02). This algorithm represents an important advancement in quantifying non-occupational pesticide relative exposure differences and will facilitate improved etiologic analyses in the AHS spouses. The algorithm could be adapted to studies with similar information.

Background: Exposure to bisphenol A (BPA) can be assessed using external and internal exposure measures. We examined the relationship between two measures of external BPA exposure (air and hand-wipe samples) and one of internal exposure (total BPA in urine) for a group of US manufacturing workers. Methods: During 2013-2014, we recruited 78 workers from six US companies that made BPA or made products with BPA. We quantified BPA in seven urine samples, two full-shift air samples and in pre- and end-shift hand-wipe samples collected from workers over 2 consecutive days. We examined correlations between creatinine-corrected urinary concentrations of total BPA (total BPACR) and BPA levels in air and hand wipes using Pearson's correlation coefficient. We also applied mixed-effects regression models to examine the relationship between total BPACR with BPA in air (urine~air model) and with BPA in end-shift hand wipes (urine~hand model), separately and together (urine~air+hand model), after adjusting for covariates. Results: End-shift total BPACR strongly correlated with BPA in air (rp = 0.79, P < 0.0001) and nearly as strongly with BPA in end-shift hand wipes (rp = 0.75, P < 0.0001). In mixed-effect models, BPA air concentration and end-shift hand-wipe BPA level were significantly and positively associated with end-shift total BPACR (P < 0.0001 each). We found a significant effect of the Day 1 BPA air concentration on Day 2 total BPACR (P = 0.0104). When BPA air concentration and end-shift hand-wipe BPA level were in the same model, the air concentration (P < 0.0001) was more significant than the hand-wipe level (P = 0.0106). Conclusion: BPA levels in air and end-shift hand wipes strongly correlated with total BPACR, suggesting that both inhalation and dermal contract were likely exposure routes; however, inhalation, on average, appeared to be a more dominant exposure route than dermal contact for these manufacturing workers.

For decades, bisphenol A (BPA) has been used in making polycarbonate, epoxy, and phenolic resins and certain investment casting waxes, yet published exposure data are lacking for U.S. manufacturing workers. In 2013-2014, BPA air and hand exposures were quantified for 78 workers at six U.S. companies making BPA or BPA-based products. Exposure measures included an inhalable-fraction personal air sample on each of two consecutive work days (n = 146), pre- and end-shift hand wipe samples on the second day (n = 74 each), and surface wipe samples (n = 88). Potential determinants of BPA air and end-shift hand exposures (after natural log transformation) were assessed in univariate and multiple regression mixed models. The geometric mean (GM) BPA air concentration was 4.0 microg/m3 (maximum 920 microg/m3). The end-shift GM BPA hand level (26 microg/sample) was 10-times higher than the pre-shift level (2.6 microg/sample). BPA air and hand exposures differed significantly by industry and job. BPA air concentrations and end-shift hand levels were highest in the BPA-filled wax manufacturing/reclaim industry (GMAir = 48 microg/m3, GMHand-End = 130 microg/sample) and in the job of working with molten BPA-filled wax (GMAir = 43 microg/m3, GMHand-End = 180 microg/sample), and lowest in the phenolic resins industry (GMAir = 0.85 microg/m3, GMHand-End = 0.43 microg/sample) and in the job of flaking phenolic resins (GMAIR = 0.62 microg/m3, GMHand-End = 0.38 microg/sample). Determinants of increased BPA air concentration were industry, handling BPA containers, spilling BPA, and spending ≥50% of the shift in production areas; increasing age was associated with lower air concentrations. BPA hand exposure determinants were influenced by high values for two workers; for all other workers, tasks involving contact with BPA-containing materials and spending ≥50% of the shift in production areas were associated with increased BPA hand levels. Surface wipe BPA levels were significantly lower in eating/office areas (GM = 9.3 microg/100 cm2) than in production areas (GM = 140 microg/100 cm2). In conclusion, worker BPA exposure was associated with tasks and conditions affecting both inhalation and dermal exposure. The potential for BPA-related health effects among these workers is unknown.

Background: Bisphenol A (BPA) toxicity and exposure risk to humans has been the subject of considerable scientific debate; however, published occupational exposure data for BPA are limited. Methods: In 2013–2014, 77 workers at six US companies making BPA, BPA-based resins, or BPA-filled wax provided seven urine samples over two consecutive work days (151 worker-days, 525 samples). Participant information included industry, job, tasks, personal protective equipment used, hygiene behaviors, and canned food/beverage consumption. Total (free plus conjugated) BPA, quantified in urine by mass spectrometry, was detected in all samples. Results:The geometric mean (GM) creatinine-adjusted total BPA (total BPACR) concentration was 88.0 microg g−1 (range 0.78–18900 microg g - 1), approximately 70 times higher than in US adults in 2013–2014 (1.27 microg g-1). GM total BPACR increased during Day 1 (26.6-127 microg g- 1), decreased by pre-shift Day 2 (84.4 microg g - 1) then increased during Day 2 to 178 microg - 1. By industry, baseline and post-baseline total BPACR was highest in BPA-filled wax manufacturing/reclaim (GM = 111 microg g - 1) and lowest in phenolic resin manufacturing (GM = 6.56 microg g-1). By job, total BPACR was highest at baseline in maintenance workers (GM = 157 microg g−1) and post-baseline in those working with molten BPA-filled wax (GM = 441 microg g - 1). Workers in the job of flaking a BPA-based resin had the lowest concentrations at baseline (GM = 4.81 microg g−1) and post-baseline (GM = 23.2 µg g−1). In multiple regression models, at baseline, industry significantly predicted increased total BPACR (P = 0.0248); post-baseline, handling BPA containers (P = 0.0035), taking ≥3 process/bulk samples with BPA (P = 0.0002) and wearing a Tyvek coverall (P = 0.0042) significantly predicted increased total BPACR (after adjusting for total BPACR at baseline, time point, and body mass index). Conclusion: Several work-related factors, including industry, job, and certain tasks performed, were associated with increased urinary total BPACR concentrations in this group of manufacturing workers. The potential for BPA-related health effects among these workers is unknown.

BACKGROUND: Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. OBJECTIVE: To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. METHODS: From studies in North American agricultural areas published from 1995-2015, we abstracted dust pesticide concentrations reported as summary statistics (e.g., geometric means (GM)). We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). RESULTS: For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (inter-quartile range of published data) based on 52 statistics from 7 studies. For the para-occupational pathway, GMs were 2.3 times higher (95% confidence interval [CI]: 1.5-3.3; 15 statistics, 5 studies) in homes of farmers who applied pesticides more versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95%CI: 1.1-1.4) and 1.5 (95%CI: 1.2-1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and ≥20%, respectively (88 statistics, 5 studies). CONCLUSION: Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available.

BACKGROUND: Occupational pesticide use is associated with lung cancer in some, but not all, epidemiologic studies. In the Agricultural Health Study (AHS), we previously reported positive associations between several pesticides and lung cancer incidence. OBJECTIVE: We evaluated use of 43 pesticides and 654 lung cancer cases after ten years of additional follow-up in the AHS, a prospective cohort study comprised of 57,310 pesticide applicators from Iowa and North Carolina. METHODS: Information about lifetime pesticide use and other factors was ascertained at enrollment (1993-1997) and updated with a follow-up questionnaire (1999-2005). Cox proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for smoking (smoking status and pack-years), gender, and lifetime days of use of any pesticides. RESULTS: Hazard ratios were elevated in the highest exposure category of lifetime days of use for pendimethalin (1.50; 95% CI = 0.98-2.31), dieldrin (1.93; 95% CI = 0.70-5.30), and chlorimuron-ethyl (1.74; 95% CI = 1.02-2.96), although monotonic exposure-response gradients were not evident. The HRs for intensity-weighted lifetime days of use of these pesticides were similar. For parathion, the trend was statistically significant for intensity-weighted lifetime days (p=0.049) and borderline for lifetime days (p=0.073). None of the remaining pesticides evaluated were associated with lung cancer incidence. CONCLUSIONS: These analyses provide additional evidence for an association between pendimethalin, dieldrin, and parathion use and lung cancer risk. We found an association between chlorimuron-ethyl, a herbicide introduced in 1986, and lung cancer that has not been previously reported. Continued follow-up is warranted.

Metolachlor, a widely used herbicide, is classified as a Group C carcinogen by the U.S. Environmental Protection Agency based on increased liver neoplasms in female rats. Epidemiologic studies of the health effects of metolachlor have been limited. The Agricultural Health Study (AHS) is a prospective cohort study including licensed private and commercial pesticide applicators in Iowa and North Carolina enrolled 1993-7. We evaluated cancer incidence through 2010/2011 (NC/IA) for 49,616 applicators, 53% of whom reported ever using metolachlor. We used Poisson regression to evaluate relations between two metrics of metolachlor use (lifetime days, intensity-weighted lifetime days) and cancer incidence. We saw no association between metolachlor use and incidence of all cancers combined (n=5701 with a 5-year lag) or most site-specific cancers. For liver cancer, in analyses restricted to exposed workers, elevations observed at higher categories of use were not statistically significant. However, trends for both lifetime and intensity-weighted lifetime days of metolachor use were positive and statistically significant with an unexposed reference group. A similar pattern was observed for follicular-cell lymphoma, but no other lymphoma subtypes. An earlier suggestion of increased lung cancer risk at high levels of metolachlor use in this cohort was not confirmed in this update. This suggestion of an association between metolachlor and liver cancer among pesticide applicators is a novel finding and echoes observation of increased liver neoplasms in some animal studies. However, our findings for both liver cancer and follicular-cell lymphoma warrant follow-up to better differentiate effects of metolachlor use from other factors.

BACKGROUND: Women living in agricultural areas may experience high pesticide exposures compared to women in urban or suburban areas due to their proximity to farm activities. OBJECTIVE: Our objective was to review the evidence in the published literature for the contribution of nonoccupational pathways of pesticide exposure in women living in North American agricultural areas. METHODS: We evaluated the following nonoccupational exposure pathways: para-occupational (i.e., take-home or bystander exposure), agricultural drift, residential pesticide use, and dietary ingestion. We also evaluated the role of hygiene factors (e.g., house cleaning; shoe removal). RESULTS: Among 35 publications identified (published 1995-2013), several reported significant or suggestive (p<0.1) associations between para-occupational (n=19) and agricultural drift (n=10) pathways and pesticide dust or biomarker levels, while three observed that residential use was associated with pesticide concentrations in dust. The four studies related to ingestion reported low detection rates of most pesticides in water; additional studies are needed to draw conclusions about this pathway's importance. Hygiene factors were not consistently linked to exposure among the 18 relevant publications identified. CONCLUSIONS: Evidence supported the importance of para-occupational, drift, and residential use pathways. Disentangling exposure pathways was difficult because agricultural populations are concurrently exposed to pesticides via multiple pathways. Most evidence was based on measurements of pesticides in residential dust, which are applicable to any household member and are not specific to women. An improved understanding of nonoccupational pesticide exposure pathways in women living in agricultural areas is critical for studying health effects in women and for designing effective exposure-reduction strategies.

Since its registration in 1994 acetochlor has become a commonly used herbicide in the US, yet no epidemiologic study has evaluated its carcinogenicity in humans. We evaluated the use of acetochlor and cancer incidence among licensed pesticide applicators in the Agricultural Health Study. In telephone interviews administered during 1999-2005, participants provided information on acetochlor use, use of other pesticides and additional potential confounders. We used Poisson regression to estimate relative risks (RR) and 95% confidence intervals (95% CI) for cancers that occurred from the time of interview through 2011 in Iowa and 2010 in North Carolina. Among 33,484 men, there were 4,026 applicators who used acetochlor and 3,234 incident cancers, with 304 acetochlor-exposed cases. Increased risk of lung cancer was observed among acetochlor users (RR = 1.74; 95% CI: 1.07-2.84) compared to nonusers, and among individuals who reported using acetochlor/atrazine product mixtures (RR = 2.33; 95% CI: 1.30-4.17), compared to nonusers of acetochlor. Colorectal cancer risk was significantly elevated among the highest category of acetochlor users (RR = 1.75; 95% CI: 1.08-2.83) compared to never users. Additionally, borderline significantly increased risk of melanoma (RR = 1.61; 95% CI: 0.98-2.66) and pancreatic cancer (RR = 2.36; 95% CI: 0.98-5.65) were observed among acetochlor users. The associations between acetochlor use and lung cancer, colorectal cancer, melanoma and pancreatic cancer are suggestive, however the lack of exposure-response trends, small number of exposed cases and relatively short time between acetochlor use and cancer development prohibit definitive conclusions.

Prospective cohorts have played a major role in understanding the contribution of diet, physical activity, medical conditions, and genes to the development of many diseases, but have not been widely used for occupational exposures. Studies in agriculture are an exception. We draw upon our experience using this design to study agricultural workers to identify conditions that might foster use of prospective cohorts to study other occupational settings. Prospective cohort studies are perceived by many as the strongest epidemiologic design. It allows updating of information on exposure and other factors, collection of biologic samples before disease diagnosis for biomarker studies, assessment of effect modification by genes, lifestyle, and other occupational exposures, and evaluation of a wide range of health outcomes. Increased use of prospective cohorts would be beneficial in identifying hazardous exposures in the workplace. Occupational epidemiologists should seek opportunities to initiate prospective cohorts to investigate high priority, occupational exposures.

Farming and pesticide use have previously been linked to non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). We evaluated agricultural use of specific insecticides, fungicides, and fumigants and risk of NHL and NHL-subtypes (including CLL and MM) in a U.S.-based prospective cohort of farmers and commercial pesticide applicators. A total of 523 cases occurred among 54,306 pesticide applicators from enrollment (1993-97) through December 31, 2011 in Iowa, and December 31, 2010 in North Carolina. Information on pesticide use, other agricultural exposures and other factors was obtained from questionnaires at enrollment and at follow-up approximately five years later (1999-2005). Information from questionnaires, monitoring, and the literature were used to create lifetime-days and intensity-weighted lifetime days of pesticide use, taking into account exposure-modifying factors. Poisson and polytomous models were used to calculate relative risks (RR) and 95% confidence intervals (CI) to evaluate associations between 26 pesticides and NHL and five NHL-subtypes, while adjusting for potential confounding factors. For total NHL, statistically significant positive exposure-response trends were seen with lindane and DDT. Terbufos was associated with total NHL in ever/never comparisons only. In subtype analyses, terbufos and DDT were associated with small cell lymphoma/chronic lymphocytic leukemia/marginal cell lymphoma, lindane and diazinon with follicular lymphoma, and permethrin with MM. However, tests of homogeneity did not show significant differences in exposure-response among NHL-subtypes for any pesticide. Because 26 pesticides were evaluated for their association with NHL and its subtypes, some chance finding could have occurred. Our results showed pesticides from different chemical and functional classes were associated with an excess risk of NHL and NHL subtypes, but not all members of any single class of pesticides were associated with an elevated risk of NHL or NHL subtypes. These findings are among the first to suggest links between DDT, lindane, permethrin, diazinon and terbufos with NHL subtypes.

Indium use has increased greatly in the past decade in parallel with the growth of flat-panel displays, touchscreens, optoelectronic devices, and photovoltaic cells. Much of this growth has been in the use of indium tin oxide (ITO). This increased use has resulted in more frequent and intense exposure of workers to indium. Starting with case reports and followed by epidemiological studies, exposure to ITO has been linked to serious and sometimes fatal lung disease in workers. Much of this research was conducted in facilities that process sintered ITO, including manufacture, grinding, and indium reclamation from waste material. Little has been known about indium exposure to workers in downstream applications. In 2009-2011, the National Institute for Occupational Safety and Health (NIOSH) contacted 89 potential indium-using companies; 65 (73%) responded, and 43 of the 65 responders used an indium material. Our objective was to identify current workplace applications of indium materials, tasks with potential indium exposure, and exposure controls being used. Air sampling for indium was either conducted by NIOSH or companies provided their data for a total of 63 air samples (41 personal, 22 area) across 10 companies. Indium exposure exceeded the NIOSH recommended exposure limit (REL) of 0.1 mg/m(3) for certain methods of resurfacing ITO sputter targets, cleaning sputter chamber interiors, and in manufacturing some inorganic indium compounds. Indium air concentrations were low in sputter target bonding with indium solder, backside thinning and polishing of fabricated indium phosphide-based semiconductor devices, metal alloy production, and in making indium-based solder pastes. Exposure controls such as containment, local exhaust ventilation (LEV), and tool-mounted LEV can be effective at reducing exposure. In conclusion, occupational hygienists should be aware that the manufacture and use of indium materials can result in indium air concentrations that exceed the NIOSH REL. Given recent findings of adverse health effects in workers, research is needed to determine if the current REL sufficiently protects workers against indium-related diseases.

The disaster environment frequently presents rapidly evolving and unpredictable hazardous exposures to emergency responders. Improved estimates of exposure and effect from biomonitoring can be used to assess exposure-response relationships, potential health consequences, and effectiveness of control measures. Disaster settings, however, pose significant challenges for biomonitoring. A decision process for determining when to conduct biomonitoring during and following disasters was developed. Separate but overlapping decision processes were developed for biomonitoring performed as part of occupational health investigations that directly benefit emergency responders in the short term and for biomonitoring intended to support research studies. Two categories of factors critical to the decision process for biomonitoring were identified: Is biomonitoring appropriate for the intended purpose and is biomonitoring feasible under the circumstances of the emergency response? Factors within these categories include information needs, relevance, interpretability, ethics, methodology, and logistics. Biomonitoring of emergency responders can be a valuable tool for exposure and risk assessment. Information needs, relevance, and interpretability will largely determine if biomonitoring is appropriate; logistical factors will largely determine if biomonitoring is feasible. The decision process should be formalized and may benefit from advance planning.

Organophosphorous insecticides (OPs) are the most commonly used insecticides in US agriculture, but little information is available regarding specific OP use by individual farmers. We describe OP use for licensed private pesticide applicators from Iowa and North Carolina in the Agricultural Health Study (AHS) using lifetime pesticide use data from 701 randomly selected male participants collected at three time periods. Of 27 OPs studied, 20 were used by >1%. Overall, 95% had ever applied at least one OP. The median number of different OPs used was 4 (maximum=13). Malathion was the most commonly used OP (74%) followed by chlorpyrifos (54%). OP use declined over time. At the first interview (1993-1997), 68% of participants had applied OPs in the past year; by the last interview (2005-2007), only 42% had. Similarly, median annual application days of OPs declined from 13.5 to 6 days. Although OP use was common, the specific OPs used varied by state, time period, and individual. Much of the variability in OP use was associated with the choice of OP, rather than the frequency or duration of application. Information on farmers' OP use enhances our ability to characterize and understand the potential health effects of multiple OP exposures.

Pesticide exposures can be reduced by use of personal protective equipment as well as proper mixing and application practices. The authors examined the effects of risk-accepting personality on personal protective equipment (PPE) use and mixing and application practices among private pesticide applicators and their spouses within the Agricultural Health Study (AHS) in Iowa and North Carolina and commercial applicators in Iowa. The AHS follow-up questionnaire included four questions designed to assess attitudes toward risk. Analysis was limited to those who were currently working on a farm or registered as a commercial applicator and indicated current pesticide use (n = 25,166). Respondents who answered three or more questions in the affirmative (private applicators: n = 4160 [21%]; commercial applicators: n = 199 [14%]; spouses: n = 829 [23%]) were classified as having a risk-accepting personality. Logistic regression was used to evaluate specific work practices associated with risk-accepting attitudes. Among private applicators, the likelihood of using any PPE when mixing or loading pesticides was lower among risk-acceptors compared to risk-averse individuals (odds ratio [OR] = 0.72, 95% confidence interval [CI]: 0.65-0.79). A similar relationship was observed among commercial applicators (OR = 0.77, 95% CI: 0.34-1.77) but not among spouses (OR = 1.09, 95% CI: 0.90-1.33). Among private applicators, risk-acceptors were more likely than the risk-averse to apply pesticides within 50 feet of the home (OR = 1.21, 95% CI: 1.01-1.44), compared to further than (1/4) mile. These findings suggest that the decisions to use personal protective equipment and properly handle/apply pesticides may be driven by risk-accepting personality traits. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Agromedicine for the following free supplemental resource: Adjusted odds ratios of PPE use and risk accepting personality traits among participants currently applying pesticides in the Agricultural Health Study (1999-2005)].

The Agricultural Health Study (AHS), a large prospective cohort, was designed to elucidate associations between pesticide use and other agricultural exposures and health outcomes. The cohort includes 57,310 pesticide applicators who were enrolled between 1993 and 1997 in Iowa and North Carolina. A follow-up questionnaire administered 5 years later was completed by 36,342 (63%) of the original participants. Missing pesticide use information from participants who did not complete the second questionnaire impedes both long-term pesticide exposure estimation and statistical inference of risk for health outcomes. Logistic regression and stratified sampling were used to impute key variables related to the use of specific pesticides for 20,968 applicators who did not complete the second questionnaire. To assess the imputation procedure, a 20% random sample of participants was withheld for comparison. The observed and imputed prevalence of any pesticide use in the holdout dataset were 85.7% and 85.3%, respectively. The distribution of prevalence and days/year of use for specific pesticides were similar across observed and imputed in the holdout sample. When appropriately implemented, multiple imputation can reduce bias and increase precision and can be more valid than other missing data approaches.

An algorithm developed to estimate pesticide exposure intensity for use in epidemiologic analyses was revised based on data from two exposure monitoring studies. In the first study, we estimated relative exposure intensity based on the results of measurements taken during the application of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) (n = 88) and the insecticide chlorpyrifos (n = 17). Modifications to the algorithm weighting factors were based on geometric means (GM) of post-application urine concentrations for applicators grouped by application method and use of chemically-resistant (CR) gloves. Measurement data from a second study were also used to evaluate relative exposure levels associated with airblast as compared to hand spray application methods. Algorithm modifications included an increase in the exposure reduction factor for use of CR gloves from 40% to 60%, an increase in the application method weight for boom spray relative to in-furrow and for air blast relative to hand spray, and a decrease in the weight for mixing relative to the new weights assigned for application methods. The weighting factors for the revised algorithm now incorporate exposure measurements taken on Agricultural Health Study (AHS) participants for the application methods and personal protective equipment (PPE) commonly reported by study participants.

BACKGROUND: Atrazine is a triazine herbicide used widely in the United States. Although it is an animal carcinogen, the mechanism in rodents does not appear to operate in humans. Few epidemiologic studies have provided evidence for an association. METHODS: The Agricultural Health Study (AHS) is a prospective cohort that includes 57,310 licensed pesticide applicators. In this report, we extend a previous AHS analysis of cancer risk associated with self-reported atrazine use with six additional years of follow-up and more than twice as many cancer cases. Using Poisson regression, we calculated relative risk estimates and 95% confidence intervals for lifetime use of atrazine and intensity-weighted lifetime days, which accounts for factors that impact exposure. RESULTS: Overall, 36,357 (68%) of applicators reported using atrazine, among whom there were 3,146 cancer cases. There was no increase among atrazine users in overall cancer risk or at most cancer sites in the higher exposure categories compared with the lowest. Based on 29 exposed cases of thyroid cancer, there was a statistically significant risk in the second and fourth quartiles of intensity-weighted lifetime days. There was a similar pattern for lifetime days, but neither the risk estimates nor the trend were statistically significant and for neither metric was the trend monotonic. CONCLUSIONS: Overall, there was no consistent evidence of an association between atrazine use and any cancer site. There was a suggestion of increased risk of thyroid cancer, but these results are based on relatively small numbers and minimal supporting evidence.

OBJECTIVES: To identify and quantify determinants of captan exposure among 74 private orchard pesticide applicators in the Agricultural Health Study (AHS). To adjust an algorithm used for estimating pesticide exposure intensity in the AHS based on these determinants and to compare the correlation of the adjusted and unadjusted algorithms with urinary captan metabolite levels. METHODS: External exposure metrics included personal air, hand rinse, and dermal patch samples collected from each applicator on 2 days in 2002-2003. A 24-h urine sample was also collected. Exposure determinants were identified for each external metric using multiple linear regression models via the NLMIXED procedure in SAS. The AHS algorithm was adjusted, consistent with the identified determinants. Mixed-effect models were used to evaluate the correlation between the adjusted and unadjusted algorithm and urinary captan metabolite levels. RESULTS: Consistent determinants of captan exposure were a measure of application size (kilogram of captan sprayed or application method), wearing chemical-resistant (CR) gloves and/or a coverall/suit, repairing spray equipment, and product formulation. Application by airblast was associated with a 4- to 5-fold increase in exposure as compared to hand spray. Exposure reduction to the hands, right thigh, and left forearm from wearing CR gloves averaged approximately 80%, to the right and left thighs and right forearm from wearing a coverall/suit by approximately 70%. Applicators using wettable powder formulations had significantly higher air, thigh, and forearm exposures than those using liquid formulations. Application method weights in the AHS algorithm were adjusted to nine for airblast and two for hand spray; protective equipment reduction factors were adjusted to 0.2 (CR gloves), 0.3 (coverall/suit), and 0.1 (both). CONCLUSIONS: Adjustment of application method, CR glove, and coverall weights in the AHS algorithm based on our exposure determinant findings substantially improved the correlation between the AHS algorithm and urinary metabolite levels.

PURPOSE: Diisononyl phthalate (DiNP) is primarily used as a plasticizer in polyvinyl chloride (PVC) materials. While information is available on general population exposure to DiNP, occupational exposure data are lacking. We present DiNP metabolite urinary concentrations in PVC processing workers, estimate DiNP daily intake for these workers, and compare worker estimates to other populations. METHODS: We assessed DiNP exposure in participants from two companies that manufactured PVC materials, a PVC film manufacturer (n = 25) and a PVC custom compounder (n = 12). A mid-shift and end-shift urine sample was collected from each participant and analyzed for the DiNP metabolite mono(carboxy-isooctyl) phthalate (MCiOP). Mixed models were used to assess the effect on MCiOP concentrations of a worker being assigned to (1) a task using DiNP and (2) a shift where DiNP was used. A simple pharmacokinetic model was used to estimate DiNP daily intake from the MCiOP concentrations. RESULTS: Creatinine-adjusted MCiOP urinary concentrations ranged from 0.42-80 mcg/g in PVC film and from 1.11-13.4 mcg/g in PVC compounding. PVC film participants who worked on a task using DiNP (n = 7) had the highest MCiOP geometric mean (GM) end-shift concentration (25.2 mcg/g), followed by participants who worked on a shift where DiNP was used (n = 11) (17.7 mcg/g) as compared to participants with no task (2.92 mcg/g) or shift (2.08 mcg/g) exposure to DiNP. The GM end-shift MCiOP concentration in PVC compounding participants (4.80 mcg/g) was comparable to PVC film participants with no task or shift exposure to DiNP. Because no PVC compounding participants were assigned to tasks using DINP on the day sampled, DiNP exposure in this company may be underestimated. The highest DiNP intake estimate was 26 mcg/kg/day. CONCLUSION: Occupational exposure to DiNP associated with PVC film manufacturing tasks were substantially higher (sixfold to tenfold) than adult general population exposures; however, all daily intake estimates were less than 25% of current United States or European acceptable or tolerable daily intake estimates. Further characterization of DiNP occupational exposures in other industries is recommended.

BACKGROUND: The Agricultural Health Study (AHS) is a prospective study of licensed pesticide applicators and their spouses in Iowa and North Carolina. We evaluate the impact of occupational pesticide exposure misclassification on relative risks using data from the cohort and the AHS Pesticide Exposure Study (AHS/PES). METHODS: We assessed the impact of exposure misclassification on relative risks using the range of correlation coefficients observed between measured post-application urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) and a chlorpyrifos metabolite and exposure estimates based on an algorithm from 83 AHS pesticide applications. RESULTS: Correlations between urinary levels of 2,4-D and a chlorpyrifos metabolite and algorithm estimated intensity scores were about 0.4 for 2,4-D (n=64), 0.8 for liquid chlorpyrifos (n=4) and 0.6 for granular chlorpyrifos (n=12). Correlations of urinary levels with kilograms of active ingredient used, duration of application, or number of acres treated were lower and ranged from -0.36 to 0.19. These findings indicate that a priori expert-derived algorithm scores were more closely related to measured urinary levels than individual exposure determinants evaluated here. Estimates of potential bias in relative risks based on the correlations from the AHS/PES indicate that non-differential misclassification of exposure using the algorithm would bias estimates towards the null, but less than that from individual exposure determinants. CONCLUSIONS: Although correlations between algorithm scores and urinary levels were quite good (ie, correlations between 0.4 and 0.8), exposure misclassification would still bias relative risk estimates in the AHS towards the null and diminish study power.

Comparing agricultural cohorts with the general population is challenging because the general healthiness of farmers may mask potential adverse health effects of farming. Using data from the Agricultural Health Study, a cohort of 89,656 pesticide applicators and their spouses (N = 89, 656) in North Carolina and Iowa, the authors computed standardized mortality ratios (SMRs) comparing deaths from time of the enrollment (1993-1997) through 2007 to state-specific rates. To compensate for the cohort's overall healthiness, relative SMRs were estimated by calculating the SMR for each cause relative to the SMR for all other causes. In 1,198,129 person-years of follow-up, 6,419 deaths were observed. The all-cause mortality rate was less than expected (SMR(applicators) = 0.54, 95% confidence interval (CI): 0.52, 0.55; SMR(spouses) = 0.52, 95% CI: 0.50, 0.55). SMRs for all cancers, heart disease, and diabetes were significantly below 1.0. In contrast, applicators experienced elevated numbers of machine-related deaths (SMR = 4.15, 95% CI: 3.18, 5.31), motor vehicle nontraffic accidents (SMR = 2.80, 95% CI: 1.81, 4.14), and collisions with objects (SMR = 2.12, 95% CI: 1.25, 3.34). In the relative SMR analysis for applicators, the relative mortality ratio was elevated for lymphohematopoietic cancers, melanoma, and digestive system, prostate, kidney, and brain cancers. Among spouses, relative SMRs exceeded 1.0 for lymphohematopoietic cancers and malignancies of the digestive system, brain, breast, and ovary. Unintentional fatal injuries remain an important risk for farmers; mortality ratios from several cancers were elevated relative to other causes.

Studies of determinants of occupational exposure frequently involve left-censored lognormally distributed data, often with repeated measures. Left censoring occurs when observations are below the analytical limit of detection (LOD); repeated measures data results from taking multiple measurements on the same worker. A common method of dealing with this type of data has been to substitute a value (such as LOD/2) for the censored data followed by statistical analysis using the 'usual' methods. Recently, maximum likelihood estimation (MLE) methods have been employed to reduce bias associated with the substitution method. We compared substitution and MLE methods using simulated lognormally distributed exposure data subjected to varying amounts of censoring using two procedures available in SAS: LIFEREG and NLMIXED. In these simulations, the MLE method resulted in less bias and performed well even for censoring up to 80%, whereas the substitution method resulted in considerable bias. We illustrate the NLMIXED procedure using a dataset of chlorpyrifos air measurements collected from termiticide applicators on consecutive days over a 5-day workweek. We provide sample SAS code for several situations including one and two groups, with and without repeated measures, random slopes, and nested random effects.

OBJECTIVES: There are some common occupational agents and exposure circumstances where evidence of carcinogenicity is substantial but not yet conclusive for humans. The objectives are to identify research gaps and needs for twenty agents prioritized for review based on evidence of widespread human exposures and potential carcinogenicity in animals or humans. DATA SOURCES: A systematic review was conducted of new data published since the most recent pertinent IARC monograph meeting. DATA EXTRACTION: Reviewers were charged with identifying data gaps and general and specific approaches to address them, focusing on research that would be important in resolving classification uncertainties. An expert meeting brought reviewers together to discuss each agent and the identified data gaps and approaches. DATA SYNTHESIS: Several overarching issues were identified that pertained to multiple agents; these included the importance of recognizing that carcinogenic agents can act through multiple toxicity pathways and mechanisms, including epigenetic mechanisms, oxidative stress and immuno- and hormonal modulation. CONCLUSIONS: Studies in occupational populations provide important opportunities to understand the mechanisms through which exogenous agents cause cancer and intervene to prevent human exposure and/or prevent or detect cancer among those already exposed. Scientific developments are likely to increase the challenges and complexities of carcinogen testing and evaluation in the future, and epidemiologic studies will be particularly critical to inform carcinogen classification and risk assessment processes.

Phthalates are used as plasticizers in many industrial and consumer products. Urinary biomonitoring has shown widespread human exposure to phthalates, with workers having especially high exposures. Phthalates can be present in workplace air as either aerosols or vapors depending on source materials, vapor pressure, and processing temperatures. We sought to develop a dual-phase air sampling method for 6 phthalates, dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP), benzyl butyl phthalate (BzBP), di(2-ethylhexyl) phthalate (DEHP), and di-n-octyl phthalate (DnOP), adaptable to aerosol inlets with known particle collection characteristics. Collection media consisted of a quartz fiber filter and XAD-2 resin. Limit of detection (LOD) and limit of quantification (LOQ) were determined for each phthalate. Phthalate recoveries were evaluated at 3x, 10x and 30x the LOQ, and after storage at -21 degrees C and 21 degrees C. Media were Soxhlet extracted in 10% diethyl ether in hexanes along with an extraction surrogate, di-n-pentyl phthalate-d(4). Gas chromatography/mass spectrometry was performed to quantify the phthalate diesters using di(2-ethylhexyl) phthalate-d(4) as an internal standard. Estimated LODs were 1 microg per sample (BzBP, DEHP, and DnOP), 2 microg per sample (DMP and DBP), and 5 microg per sample (DEP). Mean recoveries under static conditions were 85-104% for DBP, BzBP, DEHP, and DnOP; but <70% for DMP and DEP at 3x and 10x the LOQ. After air was pulled through spiked samples, DMP and DEP recoveries improved to 74-81%. After storage for 62 days, phthalate recovery was better at -21 degrees C than at 21 degrees C. Method accuracy was best for DBP, BzBP, DEHP, and DnOP (range 11-18%), and less so for DMP (28%) and DEP (29%).

Improved analytical methods for measuring urinary phthalate metabolites have resulted in biomarker-based estimates of phthalate daily intake for the general population, but not for occupationally exposed groups. In 2003-2005, we recruited 156 workers from eight industries where materials containing diethyl phthalate (DEP), dibutyl phthalate (DBP), and/or di(2-ethylhexyl) phthalate (DEHP) were used as part of the worker's regular job duties. Phthalate metabolite concentrations measured in the workers' end-shift urine samples were used in a simple pharmacokinetic model to estimate phthalate daily intake. DEHP intake estimates based on three DEHP metabolites combined were 0.6-850 mug/kg/day, with the two highest geometric mean (GM) intakes in polyvinyl chloride (PVC) film manufacturing (17 mug/kg/day) and PVC compounding (12 mug/kg/day). All industries, except phthalate manufacturing, had some workers whose DEHP exposure exceeded the U.S. reference dose (RfD) of 20 mug/kg/day. A few workers also exceeded the DEHP European tolerable daily intake (TDI) of 50 mug/kg/day. DEP intake estimates were 0.5-170 mug/kg/day, with the highest GM in phthalate manufacturing (27 mug/kg/day). DBP intake estimates were 0.1-76 mug/kg/day, with the highest GMs in rubber gasket and in phthalate manufacturing (17 mug/kg/day, each). No DEP or DBP intake estimates exceeded their respective RfDs. The DBP TDI (10 mug/kg/day) was exceeded in three rubber industries and in phthalate manufacturing. These intake estimates are subject to several uncertainties; however, an occupational contribution to phthalate daily intake is clearly indicated in some industries.Journal of Exposure Science and Environmental Epidemiology advance online publication, 16 December 2009; doi:10.1038/jes.2009.62.