Literature landscape of neurodevelopment and pesticides: A scoping review of methodologies.

Pesticides are highly tested and regulated chemicals. There is currently great interest in the role that pesticides may play in childhood neurodevelopment. The objective was to identify and describe the body of evidence and to assess the ability to synthesize effect estimates. The epidemiologic literature from 2011 to 2022 was searched for publications on the association between pesticide exposure and neurodevelopment, behavior, and/or cognition in children. We identified 114 publications, representing 67 unique studies. While organochlorine and other insecticides were the most common classes of pesticides studied, up to 159 different metabolites or active ingredients were reported. Nine pesticides or their metabolites were reported in >10 publications. Similarly, multiple assessment methods were administered across studies to evaluate outcomes in neurodevelopment at ages which ranged from birth to 18 years of age. This scoping review reveals the heterogeneity among published studies with respect to exposures and health outcomes, in the methods used to assess and classify them, and in combinations of the two. This limits the adequacy of the evidence to evaluate specific risk estimates for a particular exposure-outcome pair. Intentional coordination among researchers to increase consistency in methodologies would facilitate the synthesis of results across studies. Research opportunities also exist to validate assumptions in exposure and outcome assessment which are implicit in many of the studies reviewed. In conclusion, there are many ongoing epidemiologic studies with a focus on pesticides and neurodevelopment. The variety of exposures, exposure assessment methods and tests for each outcome can be overwhelming. Interdisciplinary collaboration is recommended to harmonize data collection and to enable meaningful interpretation of the study results across populations.

Research on COVID-19 and air pollution: A path towards advancing exposure science.

The COVID-19 pandemic has resulted in an extraordinary incidence of morbidity and mortality, with almost 6 million deaths worldwide at the time of this writing (https://covid19.who.int/). There has been a pressing need for research that would shed light on factors - especially modifiable factors - that could reduce risks to human health. At least several hundred studies addressing the complex relationships among transmission of SARS-CoV-2, air pollution, and human health have been published. However, these investigations are limited by available and consistent data. The project goal was to seek input into opportunities to improve and fund exposure research on the confluence of air pollution and infectious agents such as SARS-CoV-2. Thirty-two scientists with expertise in exposure science, epidemiology, risk assessment, infectious diseases, and/or air pollution responded to the outreach for information. Most of the respondents expressed value in developing a set of common definitions regarding the extent and type of public health lockdown. Traffic and smoking ranked high as important sources of air pollution warranting source-specific research (in contrast with assessing overall ambient level exposures). Numerous important socioeconomic factors were also identified. Participants offered a wide array of inputs on what they considered to be essential studies to improve our understanding of exposures. These ranged from detailed mechanistic studies to improved air quality monitoring studies and prospective cohort studies. Overall, many respondents indicated that these issues require more research and better study design. As an exercise to solicit opinions, important concepts were brought forth that provide opportunities for scientific collaboration and for consideration for funding prioritization. Further conversations on these concepts are needed to advance our thinking on how to design research that moves us past the documented limitations in the current body of research and prepares us for the next pandemic.

Using the Matrix to bridge the epidemiology/risk assessment gap: a case study of 2,4-D.

BACKGROUND: The Matrix is designed to facilitate discussions between practitioners of risk assessment and epidemiology and, in so doing, to enhance the utility of epidemiology research for public health decision-making. The Matrix is comprised of nine fundamental "asks" of epidemiology studies, focusing on the types of information valuable to the risk assessment process. OBJECTIVE: A 2,4-dichlorophenoxyacetic acid (2,4-D) case study highlights the extent to which existing epidemiology literature includes information generally needed for risk assessments and proffers suggestions that would assist in bridging the epidemiology/risk assessment gap. METHODS: Thirty-one publications identified in the US Environmental Protection Agency 2,4-D epidemiology review were assessed. These studies focused on associations between 2,4-D exposure and non-Hodgkin lymphoma (NHL), respiratory effects, and birth outcomes. RESULTS: Many of the papers met one or more specific elements of the Matrix. However, from this case study, it is clear that some aspects of risk assessment, such as evaluating source-to-intake pathways, are generally not considered in epidemiology research. Others are incorporated, but infrequently (e.g. dose-response information, harmonization of exposure categories). We indicated where additional analyses or modifications to future study design could serve to improve the translation. DISCUSSION: Interaction with risk assessors during the study design phase and using the Matrix "asks" to guide the conversations could shape research and provide the basis for requests for funds to support these additional activities. The use of the Matrix as a foundation for communication and education across disciplines could produce more impactful and consequential epidemiology research for robust risk assessments and decision-making.

Cancer and occupational exposure to pesticides: an umbrella review.

PURPOSE: The aim was to identify the scope of the epidemiology literature reviewed regarding the risk of cancer as related to occupational exposure to pesticides and to compare regulatory toxicity results where feasible. METHODS: Review studies of breast, lung, prostate, non-Hodgkin lymphoma, and colorectal cancer were identified from the published literature from 2010 to 2020 using a priori inclusion and exclusion criteria. Epidemiology observations were first assessed and then compared against carcinogenicity profiles derived from regulatory toxicology studies. RESULTS: Several active ingredients were associated with specific cancer but overall, there was neither strong nor consistent epidemiologic data supportive of a positive association between pesticide exposure in occupational settings and cancer. Authors noted common themes related to the heterogeneity of exposure, study design, control for confounders, and the challenge to collect these data reliably and validly with an adequate sample size. Toxicology studies in laboratory animals that assessed carcinogenic potential did not reveal cancer outcomes that were concordant with reported epidemiologic findings. CONCLUSIONS: Farming and pesticides represent diverse exposures that are difficult to quantify in epidemiologic studies. Going forward, investigators will need creative and novel approaches for exposure assessment. Integration of epidemiologic and toxicological studies with attention to biological plausibility, mode of toxicological action and relevance to humans will increase the ability to better assess associations between pesticides and cancer.

Translation of Exposure and Epidemiology for Risk Assessment: A Shifting Paradigm.

Risk assessment is a well-established process used for various types of public health decision-making, such as setting chemical site clean-up levels, developing limits on exposures to chemicals in soil, water, air and food, and determining occupational exposure limits[...].

Review of 2,4-dichlorophenoxyacetic acid (2,4-D) biomonitoring and epidemiology.

A qualitative review of the epidemiological literature on the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and health after 2001 is presented. In order to compare the exposure of the general population, bystanders and occupational groups, their urinary levels were also reviewed. In the general population, 2,4-D exposure is at or near the level of detection (LOD). Among individuals with indirect exposure, i.e. bystanders, the urinary 2,4-D levels were also very low except in individuals with opportunity for direct contact with the herbicide. Occupational exposure, where exposure was highest, was positively correlated with behaviors related to the mixing, loading and applying process and use of personal protection. Information from biomonitoring studies increases our understanding of the validity of the exposure estimates used in epidemiology studies. The 2,4-D epidemiology literature after 2001 is broad and includes studies of cancer, reproductive toxicity, genotoxicity, and neurotoxicity. In general, a few publications have reported statistically significant associations. However, most lack precision and the results are not replicated in other independent studies. In the context of biomonitoring, the epidemiology data give no convincing or consistent evidence for any chronic adverse effect of 2,4-D in humans.

Mortality surveillance of a US wide cohort of chemical industry workers.

OBJECTIVE: To evaluate the mortality for an occupational cohort and discuss its suitability as an internal comparison population. METHODS: The study included 114,683 employees who worked at 1 of 25 US locations between January 1, 1960, and December 31, 2005. Standardized mortality ratios (SMRs) and 95% confidence intervals (CIs) were calculated based on US rates. RESULTS: The SMRs were significantly favorable for all causes, malignant neoplasms, heart disease, and external causes. The most common cancer sites were lung in men (SMR = 83, 95% CI = 80 to 86), and breast in women (SMR = 94, 95% CI = 80 to 111). CONCLUSIONS: Overall, the mortality rates were favorable and robust. Discussed within are topics of historical concern at specific locations that may influence the cohort's appropriateness for future studies.

Low level occupational benzene exposure and hematological parameters.

At high and prolonged exposure levels (e.g. >30 ppm), benzene can cause hematological effects. However, there is conflicting evidence on potential hematological effects at lower concentrations. We conducted a study to examine hematological effects at low benzene exposure levels in an occupational setting. Extensive exposure data and data from routine hematology examinations were available for Dow employees at the Terneuzen site in the Netherlands. We compared 8532 blood samples of Dow employees with low benzene exposure to 12,173 samples of employees with no benzene exposure that were available for the period between 1981 and 2007. Based on 21,584 benzene air measurements, a Job Exposure Matrix (JEM) was constructed for all employees with exposure. The JEM was used to estimate benzene exposure in the year in which each blood sample was collected. The average lymphocyte counts for the exposed and non-exposed group were similar. By means of mixed model regression adjustments were made for smoking, age and month of blood sample. These adjustments did not change the results and there was no indication for an adverse effect on any of the hematological parameters under investigation. A further stratification of the exposed population into three subgroups (<0.5 ppm, 0.5-1 ppm and >1 ppm) showed no significant differences for any of the hematological parameters between the three exposure categories or compared with the non-exposed group. The analysis modeling the continuous exposure effect relationship showed similar findings. This study does not indicate that workers exposed to low benzene concentrations are at an increased risk for hematological effects.

Mortality in workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin at a trichlorophenol plant in New Zealand.

OBJECTIVE: We examined the overall mortality rates of 1599 workers employed between 1969 and 1988 at a New Zealand site, which manufactured trichlorophenol. METHODS: We developed exposure estimates for 2,3,7,8-tetrachlorodibenzo-p-dioxin from a serum dioxin evaluation and used standardized mortality ratios (SMR) and proportional hazards models to evaluate risk from exposure. RESULTS: Among exposed workers, deaths from total cancers (SMR = 1.1, 95% confidence intervals [CI]: 0.9-1.4), non-Hodgkin lymphoma (SMR = 1.6, 95% CI: 03-4.7), and ischemic heart disease (SMR = 1.1, 95% CI: 0.9-1.5) were slightly greater than expected, whereas deaths from lung cancer (SMR = 0.8, 95% CI: 0.4-1.5) were less than expected. We observed no significant trends with exposure levels. CONCLUSIONS: Although this study is small, we found no increasing trend of cancer or disease risk with increasing 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure with the possible exception of all cancers combined.

Mortality in employees at a New Zealand agrochemical manufacturing site.

BACKGROUND: Previous studies at the Dow AgroSciences (Formerly Ivon Watkins-Dow) plant in New Plymouth, New Zealand, had raised concerns about the cancer risk in a subset of workers at the site with potential exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. As the plant had been involved in the synthesis and formulation of a wide range of agrochemicals and their feedstocks, we examined the mortality risk for all workers at the site. AIMS: To quantify the mortality hazards arising from employment at the Dow AgroSciences agrochemical production site in New Plymouth, New Zealand. METHODS: Workers employed between 1 January 1969 and 1 October 2003 were followed up to the end of 2004. Standardized mortality ratios (SMRs) were calculated using national mortality rates by employment duration, sex, period of hire and latency. RESULTS: A total of 1754 employees were followed during the study period and 247 deaths were observed. The all causes and all cancers SMRs were 0.97 (95% CI 0.85-1.10) and 1.01 (95% CI 0.80-1.27), respectively. Mortality due to all causes was higher for short-term workers (SMR 1.23, 95% CI 0.91-1.62) than long-term workers (SMR 0.92, 95% CI 0.80-1.06) and women had lower death rates than men. Analyses by latency and period of hire did not show any patterns consistent with an adverse impact of occupational exposures. CONCLUSIONS: The mortality experience of workers at the site was similar to the rest of New Zealand.

Evidence for the involvement of 5f orbitals in the bonding and reactivity of organometallic actinide compounds: thorium(IV) and uranium(IV) bis(hydrazonato) complexes.

Migratory insertion of diphenyldiazomethane into both metal-carbon bonds of the bis(alkyl) and bis(aryl) complexes (C(5)Me(5))(2)AnR(2) yields the first f-element bis(hydrazonato) complexes (C(5)Me(5))(2)An[eta(2)-(N,N')-R-N-N=CPh(2)](2) [An = Th, R = CH(3) (18), PhCH(2) (15), Ph (16); An = U, R = CH(3) (17), PhCH(2) (14)], which have been characterized by a combination of spectroscopy, electrochemistry, and X-ray crystallography. The two hydrazonato ligands adopt an eta(2)-coordination mode leading to 20-electron (for Th) and 22-electron (for U) complexes that have no transition-metal analogues. In fact, reaction of (C(5)H(5))(2)Zr(CH(3))(2) or (C(5)Me(5))(2)Hf(CH(3))(2) with diphenyldiazomethane is limited to the formation of the corresponding mono(hydrazonato) complex (C(5)R(5))(2)M[eta(2)-(N,N')-CH(3)-N-N=CPh(2)](CH(3)) (M = Zr, R = H or M = Hf, R = CH(3)). The difference in the reactivities of the group 4 metal complexes and the actinides was used as a unique platform for investigating in depth the role of 5f orbitals on the reactivity and bonding in actinide organometallic complexes. The electronic structure of the (C(5)H(5))(2)M[eta(2)-(N,N')-CH(3)-N-N=CH(2)](2) (M = Zr, Th, U) model complexes was studied using density functional theory (DFT) calculations and compared to experimental structural, electrochemical, and spectroscopic results. Whereas transition-metal bis(cyclopentadienyl) complexes are known to stabilize three ligands in the metallocene girdle to form saturated (C(5)H(5))(2)ML(3) species, in a bis(hydrazonato) system, a fourth ligand is coordinated to the metal center to give (C(5)H(5))(2)ML(4). DFT calculations have shown that 5f orbitals in the actinide complexes play a crucial role in stabilizing this fourth ligand by stabilizing both the sigma and pi electrons of the two eta(2)-coordinated hydrazonato ligands. In contrast, the stabilization of the hydrazonato ligands was found to be significantly less effective for the putative bis(hydrazonato) zirconium(IV) complex, yielding a higher energy structure. However, the difference in the reactivities of the group 4 metal and actinide complexes does not arise on thermodynamic grounds but is primarily of kinetic origin. Unfavorable steric factors have been ruled out as the sole influence to explain these different behaviors, and electronic factors were shown to govern the reactivity. For the actinides, both the C(5)H(5) and more realistic C(5)Me(5) ligands have been taken into account in computing the energy surface. The reaction profile for the C(5)Me(5) system differs from that with the C(5)H(5) ligand by a uniform shift of approximately 5 kcal/mol in the relative energies of the transition state and products. The insertion of a second diazoalkane molecule into the sole metal-carbon bond in the mono(hydrazonato) complexes involves a high energy barrier (approximately 20 kcal/mol) for the zirconium(IV) system, whereas the actinides can facilitate the approach of the diazoalkane by coordination (formation of an adduct) and its insertion into the An-C bond with a very low barrier on the potential energy surface.

Factors related to dioxin and furan body levels among Michigan workers.

We evaluated serum concentrations of five selected dioxin, furan, and polychlorinated biphenyls (PCB) congeners among 412 workers at a Midland, Michigan plant that manufactured trichlorophenol and pentachlorophenol (PCP) and formulated chlorophenol-based products. We examined occupational indicators of exposure to these chlorophenols taking into account intrinsic factors such as age and body fat and potential environmental sources of exposure from consumption of local game and fish and other occupations. All five congeners were significantly associated with age and body fat. 2378-TCDD serum concentrations were associated with trichlorophenol operations, total years employed at the plant, as well as working as a hazardous waste worker. 123678-H(6)CDD serum concentrations were related to occupational PCP exposure, chloracne, recent weight loss, eating local game, and working as a hazardous waste worker. Serum concentrations of PCB126 were related to smoking (inversely), and eating local fish or local game. Other factors such as diet and jobs outside of the chlorophenol plant exposures had only a very minor impact on dioxin and furan concentrations in these workers.

Dose-effect analyses of occupational chlorpyrifos exposure and peripheral nerve electrophysiology.

We performed nerve conduction studies (NCSs) on 113 chemical workers, many of whom had occupational exposure to the organophosphorus insecticide chlorpyrifos (O,O-diethyl-O-[3,5,6-trichloro-2-pyridyl]-phosphorothioate), to identify dose effects of subclinical neuropathy. In this masked longitudinal study, we estimated historic and interim chlorpyrifos exposures and measured excretion of 3,5,6 trichloro-2-pyridinol (TCP), a chlorpyrifos metabolite. TCP excretion among exposed workers suggested an estimated daily chlorpyrifos exposure averaging about 576-627 microg/day and indicated levels approximately 30% (range 0-250%) of the internal dose received by a typical subject exposed during a working day at the threshold limit value of 200 microg/m3. We modeled NCS results using linear mixed models with repeated measures. Although we found no consistent associations between interim chlorpyrifos exposure and NCS results, we identified several significant associations involving historic chlorpyrifos exposure. Most associations, however, reflected effects at low-exposure levels (< 20 mg/m3 x days) without further effects as exposure increased over a 10-fold range (20-220 mg/m3 x days). This suggested small differences among subjects with low or no chlorpyrifos exposure, rather than a dose-related deterioration among subjects with higher exposures. Two NCS results demonstrating apparent subclinical adverse dose effects showed significant but unexplained interaction with education level. The overall results provide little support for the hypothesis that chronic chlorpyrifos exposures at levels in the range associated with appreciable inhibition of B-esterases produce adverse dose effects on peripheral nerve electrophysiology suggestive of subclinical neuropathy.

Mortality study update of acrylamide workers.

OBJECTIVE: The authors examined the long-term health effects of occupational exposure to acrylamide among production and polymerisation workers. METHODS: An earlier study of 371 acrylamide workers was expanded to include employees hired since 1979. In this updated study, 696 acrylamide workers were followed from 1955 through 2001 to ascertain vital status and cause of death. Exposure to acrylamide was retrospectively assessed based on personal samples from the 1970s onwards and area samples over the whole study period. RESULTS: Fewer of the acrylamide workers died (n = 141) compared to an expected number of 172.1 (SMR 81.9, 95% CI 69.0 to 96.6). No cause-specific SMR for any of the investigated types of cancer was exposure related. The authors did, however, find more pancreatic cancer deaths than expected (SMR 222.2, 95% CI 72.1 to 518.5). With respect to non-malignant disease, more diabetes deaths were observed than expected (SMR 288.7, 95% CI 138.4 to 531.0). To assess the influence of regional factors, the analysis was repeated with an internal reference population. The elevated SMR for diabetes persisted. CONCLUSION: This study provides little evidence for a cancer risk from occupational exposure to acrylamide at production facilities. However, the increased rates of pancreatic cancer in this study and another larger study of acrylamide production workers indicate that caution is needed to rule out a cancer risk. The authors believe that the excess of diabetes mortality in this study is most likely not related to acrylamide exposure, because a larger study of acrylamide workers reported a deficit in this cause of death. The authors conclude that the increased SMR for diabetes mortality is probably not related to regional influences.

Body mass index and serum chlorinated dibenzo-p-dioxin and dibenzofuran levels.

Several studies have found that current levels of 2,3,7,8 tetrachlorodibenzo-p-dioxin in serum lipids are related to age with older persons generally having higher levels. To account for this age pattern, reference ranges based on national samples have been established in order to allow determination of background levels for regional studies. In several studies, body mass index (BMI), has also been associated with current 2,3,7,8 tetrachlorodibenzo-p-dioxin levels with increasing body mass index related to increasing levels. We measured lipid-adjusted serum levels for all 2,3,7,8-substituted dioxins and furans in 62 chemical manufacturing workers with chlorophenol exposures and 36 workers without chlorophenol exposures employed at the same location. We then assessed the impact of age and BMI on the serum levels of all these compounds in the presence of other potential confounders. We found that both factors are important independent determinants of serum levels of 2,3,7,8-substituted dioxins and furans. Specifically, age and BMI are both important factors for assessing background levels of 2,3,7,8 tetrachlorodibenzo-p-dioxin, 1,2,3,7,8 pentachlorodibenzo-p-dioxin and the calculated total toxic equivalency. BMI, but not age, is important for assessing background levels of higher chlorinated dioxins and some hexachlorofurans. We conclude that age and BMI are both important considerations when comparing a potentially exposed group to a referent group, or to national norms. Further, age and BMI may also be important in epidemiology studies where back-extrapolation from current dioxin levels is used to assess historical chlorophenol exposure.

Mortality rates among chemical workers in the Kanawha Valley of West Virginia: 1940-1999.

To expand a cohort of chemical workers in the Kanawha Valley, we conducted a study of 33,225 workers who were employed at three locations between 1940 and 1999. We observed no increase in overall cancer mortality. Higher risk estimates were observed for lymphosarcoma and reticulosarcoma among hourly employees who worked at the Institute or South Charleston locations. This finding was limited to men hired before 1960. We observed no new cases of angiosarcoma of the liver, a cause of death previously reported in association with vinyl chloride production at the South Charleston location. Specific risk factors for lymphosarcoma and reticulosarcoma have not been identified in previous targeted studies of this population and it is unlikely that additional cause-specific research will elucidate the etiology. Updates of the entire cohort will continue and can be used as a comparison population for chemical specific studies within these three plants.

Exposure misclassification in studies of agricultural pesticides: insights from biomonitoring.

BACKGROUND: Epidemiologists often assess lifetime pesticide exposure by questioning participants about use of specific pesticides and associated work practices. Recently, Dosemeci and colleagues proposed an algorithm to estimate lifetime average exposure intensity from questionnaire information. We evaluated this algorithm against measured urinary pesticide concentrations for farmers who applied glyphosate (n = 48), 2,4-D (n = 34), or chlorpyrifos (n = 34). METHODS: Algorithm scores were calculated separately based on trained field observers' and farmers' evaluations of application conditions. Statistical analyses included nonparametric correlations, assessment of categorical agreement, and categorical evaluation of exposure distributions. RESULTS: Based on field observers' assessments, there were moderate correlations between algorithm scores and urine concentrations for glyphosate (r = 0.47; 95% confidence interval [CI] = 0.21 to 0.66) and 2,4-D (0.45; 0.13 to 0.68). Correlations were lower when algorithm scores were based on participants' self-reports (for glyphosate, r = 0.23 [CI = -0.07 to 0.48]; for 2,4-D, r = 0.25 [-0.10 to 0.54]). For chlorpyrifos, there were contrasting correlations for liquid (0.42; 0.01 to 0.70) and granular formulations (-0.44; -0.83 to 0.29) based on both observers' and participants' inputs. Percent agreement in categorical analyses for the 3 pesticides ranged from 20% to 44%, and there was appreciable overlap in the exposure distributions across categories. CONCLUSIONS: Our results demonstrate the importance of collecting type of pesticide formulation and suggest a generic exposure assessment is likely to result in appreciable exposure misclassification for many pesticides.