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Bibliography Index

Lerro et al., 2020

Lerro, C. C., Andreotti, G., Wong, J. Y., Blair, A., Rothman, N., & Beane Freeman, L. E.; “2,4-D exposure and urinary markers of oxidative DNA damage and lipid peroxidation: a longitudinal study;” Occupational and Environmental Medicine, 2020, 77(4), 276-280; DOI: 10.1136/oemed-2019-106267.

ABSTRACT:

OBJECTIVE: 2,4-Dichlorophenoxyacetic acid (2,4-D) is a herbicide that is commonly used commercially, agriculturally and residentially worldwide. There is concern about its potential for carcinogenicity based on studies in laboratory animals demonstrating the potential for induction of oxidative stress. We conducted a longitudinal biomarker study of 31 pesticide applicators in Kansas who heavily applied 2,4-D and 34 non-applicator controls.

METHODS: We used multivariable generalised linear mixed-effect models to evaluate the association between urinary 2,4-D and natural log-transformed 8-iso prostaglandin F2alpha (8-isoprostane) and 8-hydroxy-2′-deoxyguanosine (8-OHdG), adjusting for urinary creatinine, age, tobacco use and concomitant use of the herbicide picloram.

RESULTS: Compared with non-applicator controls, urinary 2,4-D in the third quartile of exposure was associated with elevated 8-isoprostane (e (beta)=1.38, 95% CI 1.03 to 1.84). There was no association among the highest exposed and no exposure-response trend. 2,4-D exposure was not associated with 8-OHdG. Results were unchanged when restricted to participants who only applied 2,4-D (no picloram use).

CONCLUSIONS: We did not find evidence that increasing 2,4-D exposure was associated with 8-isoprostane or 8-OHdG. Future work should carefully evaluate potential confounders of this association, such as diet and physical activity, as well as additional biological markers of oxidative stress and damage. FULL TEXT

Lerro et al., 2020

Lerro, C. C., Hofmann, J. N., Andreotti, G., Koutros, S., Parks, C. G., Blair, A., Albert, P. S., Lubin, J. H., Sandler, D. P., & Beane Freeman, L. E.; “Dicamba use and cancer incidence in the agricultural health study: an updated analysis;” International Journal of Epidemiology, 2020; DOI: 10.1093/ije/dyaa066.

ABSTRACT:

BACKGROUND: The herbicide dicamba has been commonly used agriculturally and residentially. Recent approval of genetically engineered dicamba-resistant crops is expected to lead to increased dicamba use, and there has been growing interest in potential human health effects. A prior analysis in the Agricultural Health Study (AHS) suggested associations between dicamba and colon and lung cancer. We re-evaluated dicamba use in the AHS, including an additional 12 years and 2702 exposed cancers.

METHODS: The AHS is a prospective cohort of pesticide applicators in Iowa and North Carolina. At enrollment (1993–1997) and follow-up (1999–2005), participants reported dicamba use. Exposure was characterized by cumulative intensity-weighted lifetime days, including exposure lags of up to 20 years. We estimated relative risks (RR) and 95% confidence intervals (CI) using multivariable Poisson regression for incident cancers diagnosed from enrollment through 2014/2015.

RESULTS: Among 49 922 applicators, 26 412 (52.9%) used dicamba. Compared with applicators reporting no dicamba use, those in the highest quartile of exposure had elevated risk of liver and intrahepatic bile duct cancer (nexposed = 28, RRQ4 = 1.80, CI: 1.26–2.56, Ptrend < 0.001) and chronic lymphocytic leukaemia (CLL, nexposed = 93, RRQ4 = 1.20, CI: 0.96–1.50, Ptrend = 0.01) and decreased risk of myeloid leukaemia (nexposed = 55, RRQ4 = 0.73, CI: 0.51–1.03, Ptrend = 0.01). The associations for liver cancer and myeloid leukaemia remained after lagging exposure of up to 20 years.

CONCLUSIONS: With additional follow-up and exposure information, associations with lung and colon cancer were no longer apparent. In this first evaluation of liver and intrahepatic bile duct cancer, there was an association with increasing use of dicamba that persisted across lags of up to 20 years. FULL TEXT

Chiu, 2017

Chiu, Y. H.,”Pesticide Residues in Fruits and Vegetables: Assessment and Their Associations With Reproductive Health Outcomes;” Dissertation at Harvard Universiry, (Doctor of Science in Nutrition and Epidemiology); 2017.

ABSTRACT:

According to the Dietary Guideline, consumption of fruits and vegetables (FVs) are recommended throughout the lifespan, including during pregnancy. FVs, on the other hand, can serve as a vehicle of exposure to pesticide residues. In the US, Environmental Protection Agency (EPA) is responsible for regulating pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act and the Food Quality Protection Act. While majority of the produce sampled through the US Department of Agriculture had residues below the EPA limits, there is a growing concern whether chronic exposure to these pesticide residues may have adverse health effects, especially among susceptible populations such as pregnant women. Yet, such research is scarce. This dissertation focuses on the assessment of pesticide residues in FVs and evaluates their associations with pregnancy outcomes.

We previously have developed the Pesticide Residue Burden Score (PRBS) based on selfreported diet and national surveillance data on food pesticide residues to characterize dietary exposure over the past year. In Chapter 1, we evaluated the association of the PRBS with urinary pesticide metabolites in the Environment and Reproductive Health (EARTH) Study. We found intake of high pesticide residues FVs was positively associated with urinary concentrations of pesticide biomarkers, suggesting that PRBS can characterize dietary exposure to select pesticides.

In Chapter 2, we assessed the relation between preconception intake of high and low FVs and assisted reproductive technology outcomes in EARTH study. We found that intake of high pesticide residues FVs was associated with lower probability of clinical pregnancy and live birth, while intake of low pesticide residue FVs had the opposite relations among women undergoing infertility treatment. This is the first report of such relation in humans.

In Chapter 3, we examine the association between maternal intake of high and low pesticide residue FVs with birth outcomes in a pre-birth cohort. We found that maternal intake of high pesticide residue FVs during the first trimester was associated with higher risks of small-for-gestational-age among white women, while these exposures was associated with large-for-gestational-age among nonwhite women.

In conclusion, this work demonstrated the usefulness of PRBS in assessing pesticide residue intake through FVs. Using this method, these studies suggest exposure to pesticide residues may adversely affect pregnancy and birth outcomes.

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Chiu et al., 2015

Chiu, Y. H., Afeiche, M. C., Gaskins, a. J., Williams, P. L., Petrozza, J. C., Tanrikut, C., Hauser, R., & Chavarro, J. E.; “Fruit and vegetable intake and their pesticide residues in relation to semen quality among men from a fertility clinic;” Human Reproduction, 2015, 0, 1-10; DOI: 10.1093/humrep/dev064.

ABSTRACT:

STUDY QUESTION: Is consumption of fruits and vegetables with high levels of pesticide residues associated with lower semen quality?
Summary Answer: Consumption of fruits and vegetables with high levels of pesticide residues was associated with a lower total sperm count and a lower percentage of morphologically normal sperm among men presenting to a fertility clinic.

WHAT IS KNOWN ALREADY: Occupational and environmental exposure to pesticides is associated with lower semen quality. Whether the same is true for exposure through diet is unknown.

STUDY DESIGN, SIZE, DURATION: Men enrolled in the Environment and Reproductive Health (EARTH) Study, an ongoing prospective cohort at an academic medical fertility center. Male partners (n = 155) in subfertile couples provided 338 semen samples during 2007–2012.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen samples were collected over an 18-month period following diet assessment. Sperm concentration and motility were evaluated by computer-aided semen analysis (CASA). Fruits and vegetables were categorized as containing high or low-to-moderate pesticide residues based on data from the annual United States Department of Agriculture Pesticide Data Program. Linear mixed models were used to analyze the association of fruit and vegetable intake with sperm parameters accounting for within-person correlations across repeat samples while adjusting for potential confounders.

MAIN RESULTS AND ROLE OF CHANCE: Total fruit and vegetable intake was unrelated to semen quality parameters. High pesticide residue fruit and vegetable intake, however, was associated with poorer semen quality. On average, men in highest quartile of high pesticide residue fruit and vegetable intake (≥1.5 servings/day) had 49% (95% confidence interval (CI): 31%, 63%) lower total sperm count and 32% (95% CI: 7%, 58%) lower percentage of morphologically normal sperm than men in the lowest quartile of intake (,0.5 servings/day) (P, trend ¼ 0.003 and 0.02, respectively). Low-to-moderate pesticide residue fruit and vegetable intake was associated with a higher percentage of morphologically normal sperm (P, trend ¼ 0.04).

LIMITATIONS, REASONS FOR CAUTION: Surveillance data, rather than individual pesticide assessment,was used to assess the pesticide residue status of fruits and vegetables. CASA is a useful method for clinical evaluation but may be considered less favorable for accurate semen analysis in the research setting. Owing to the observational nature of the study, confirmation is required by interventional studies as well.

WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this is the first report on the consumption of fruits and vegetables with high levels of pesticide residue in relation to semen quality. Further confirmation of these findings is warranted.

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Curl et al., 2015

Curl, C. L., Beresford, S. A., Fenske, R. A., Fitzpatrick, A. L., Lu, C., Nettleton, J. A., & Kaufman, J. D.; “Estimating pesticide exposure from dietary intake and organic food choices: the Multi-Ethnic Study of Atherosclerosis (MESA);” Environmental Health Perspectives, 2015, 123(5), 475-483; DOI: 10.1289/ehp.1408197.

ABSTRACT:

BACKGROUND: Organophosphate pesticide (OP) exposure to the U.S. population is dominated by dietary intake. The magnitude of exposure from diet depends partly on personal decisions such as which foods to eat and whether to choose organic food. Most studies of OP exposure rely on urinary biomarkers, which are limited by short half-lives and often lack specificity to parent compounds. A reliable means of estimating long-term dietary exposure to individual OPs is needed to assess the potential relationship with adverse health effects.

OBJECTIVES: We assessed long-term dietary exposure to 14 OPs among 4,466 participants in the Multi-Ethnic Study of Atherosclerosis, and examined the influence of organic produce consumption on this exposure.

METHODS: Individual-level exposure was estimated by combining information on typical intake of specific food items with average OP residue levels on those items. In an analysis restricted to a subset of participants who reported rarely or never eating organic produce (“conventional consumers”), we assessed urinary dialkylphosphate (DAP) levels across tertiles of estimated exposure (n = 480). In a second analysis, we compared DAP levels across subgroups with differing self-reported organic produce consumption habits (n = 240).

RESULTS: Among conventional consumers, increasing tertile of estimated dietary OP exposure was associated with higher DAP concentrations (p < 0.05). DAP concentrations were also significantly lower in groups reporting more frequent consumption of organic produce (p < 0.02).

CONCLUSIONS: Long-term dietary exposure to OPs was estimated from dietary intake data, and estimates were consistent with DAP measurements. More frequent consumption of organic produce was associated with lower DAPs.

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Parron et al, 2011

Parron, T., Requena, M., Hernandez, A. F., & Alarcon, R.; “Association between environmental exposure to pesticides and neurodegenerative diseases;” Toxicology and Applied Pharmacology, 2011, 256(3), 379-385; DOI: 10.1016/j.taap.2011.05.006.

ABSTRACT:

Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer’s disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population. FULL TEXT

Hernandez et al, 2013

Hernandez, A. F., Parron, T., Tsatsakis, A. M., Requena, M., Alarcon, R., & Lopez-Guarnido, O.; “Toxic effects of pesticide mixtures at a molecular level: their relevance to human health;” Toxicology, 2013, 307, 136-145; DOI: 10.1016/j.tox.2012.06.009.

ABSTRACT:

Pesticides almost always occur in mixtures with other ones. The toxicological effects of low-dose pesticide mixtures on the human health are largely unknown, although there are growing concerns about their safety. The combined toxicological effects of two or more components of a pesticide mixture can take one of three forms: independent, dose addition or interaction. Not all mixtures of pesticides with similar chemical structures produce additive effects; thus, if they act on multiple sites their mixtures may produce different toxic effects. The additive approach also fails when evaluating mixtures that involve a secondary chemical that changes the toxicokinetics of the pesticide as a result of its increased activation or decreased detoxification, which is followed by an enhanced or reduced toxicity, respectively. This review addresses a number of toxicological interactions of pesticide mixtures at a molecular level. Examples of such interactions include the postulated mechanisms for the potentiation of pyrethroid, carbaryl and triazine herbicides toxicity by organophosphates; how the toxicity of some organophosphates can be potentiated by other organophosphates or by previous exposure to organochlorines; the synergism between pyrethroid and carbamate compounds and the antagonism between triazine herbicides and prochloraz. Particular interactions are also addressed, such as those of pesticides acting as endocrine disruptors, the cumulative toxicity of organophosphates and organochlorines resulting in estrogenic effects and the promotion of organophosphate-induced delayed polyneuropathy. FULL TEXT

Hernandez et al., 2006

Hernandez, A. F., Amparo Gomez, M., Perez, V., Garcia-Lario, J. V., Pena, G., Gil, F., Lopez, O., Rodrigo, L., Pino, G., & Pla, A.; “Influence of exposure to pesticides on serum components and enzyme activities of cytotoxicity among intensive agriculture farmers;” Environmental Research, 2006, 102(1), 70-76; DOI: 10.1016/j.envres.2006.03.002.

ABSTRACT:

Although the effects of acute pesticide poisoning are well known for the pesticides most currently used, hardly any data exist on health effects after long-term low-dose exposures. Major unresolved issues include the effect of moderate exposure in the absence of poisoning. The increased utilization of pesticides other than organophosphates makes it even more difficult to find associations. In this study a cohort of 106 intensive agriculture workers were assessed twice during the course of a spraying season for changes in serum biochemistry, namely enzymes reflecting cytotoxicity (AST, ALT, LDH, CK, and amino-oxidase) and other biochemical parameters, such as markers of nephrotoxicity (urea, creatinine) and lipid profile (cholesterol and triglycerides). Several criteria for estimating pesticide exposure were used, the most important one being serum cholinesterase depression greater than 25% from baseline to peak exposure. Our results revealed an association of pesticide exposure with changes in AST (increased activity), LDH, and amino-oxidase (decreased activity) as well as with changes in serum creatinine and phosphorus (lower and higher levels, respectively). These results provide support for a very slight impairment of the liver function, but overall these findings are consistent with no clinically significant hepatotoxicity. Intriguingly, paraoxonase-1 R allele was found to be an independent predictor of higher rates of AST and lower rates of amino-oxidase, so that it may play a supporting role as an individual marker of susceptibility on pesticide-induced health effects. In conclusion, different biomarkers might be used to detect early biochemical effects of pesticides before adverse clinical health effects occur. FULL TEXT

Backhaus and Faust, 2012

Backhaus, T., & Faust, M.; “Predictive environmental risk assessment of chemical mixtures: a conceptual framework;” Environmental Science & Technology, 2012, 46(5), 2564-2573; DOI: 10.1021/es2034125.

ABSTRACT:

Environmental risks of chemicals are still often assessed substance-by-substance, neglecting mixture effects. This may result in risk underestimations, as the typical exposure is toward multicomponent chemical “cocktails”. We use the two well established mixture toxicity concepts (Concentration Addition (CA) and Independent Action (IA)) for providing a tiered outline for environmental hazard and risk assessments of mixtures, focusing on general industrial chemicals and assuming that the “base set” of data (EC50s for algae, crustaceans, fish) is available. As mixture toxicities higher than predicted by CA are rare findings, we suggest applying CA as a precautious first tier, irrespective of the modes/mechanisms of action of the mixture components. In particular, we prove that summing up PEC/PNEC ratios might serve as a justifiable CA-approximation, in order to estimate in a first tier assessment whether there is a potential risk for an exposed ecosystem if only base-set data are available. This makes optimum use of existing single substance assessments as more demanding mixture investigations are requested only if there are first indications of an environmental risk. Finally we suggest to call for mode-of-action driven analyses only if error estimations indicate the possibility for substantial differences between CA- and IA-based assessments. FULL TEXT

Ross et al., 2013

Ross, S. M., McManus, I. C., Harrison, V., & Mason, O.; “Neurobehavioral problems following low-level exposure to organophosphate pesticides: a systematic and meta-analytic review;” Critical Reviews in Toxicology, 2013, 43(1), 21-44; DOI: 10.3109/10408444.2012.738645.

ABSTRACT:

Meta-analysis was carried out to determine the neurotoxic effects of long-term exposure to low levels of organophosphates (OPs) in occupational settings. Concern about the effects of OPs on human health has been growing as they are increasingly used throughout the world for a variety of agricultural, industrial and domestic purposes. The neurotoxic effects of acute poisoning are well established but the possibility that low-level exposure causes ill health is controversial. It is important to get a clear answer to this question as more individuals are at risk of low-level exposure than acute poisoning. Although a number of reviews on this topic have been published in the past, authors have come to conflicting conclusions. To date, none of these reviews have attempted quantitative evaluation of study findings using meta-analysis. This paper reviews the available evidence concerning the neurotoxicity of low-level occupational exposure to OPs and goes on to report the results of a meta-analysis of 14 studies which fulfilled criteria for this type of statistical analysis (means and standard deviations of dependant variables reported). Data were assimilated from more than 1600 participants. The majority of well designed studies found a significant association between low-level exposure to OPs and impaired neurobehavioral function which is consistent, small to moderate in magnitude and concerned primarily with cognitive functions such as psychomotor speed, executive function, visuospatial ability, working and visual memory. Unresolved issues in the literature which should become the focus of further studies are highlighted and discussed. FULL TEXT

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