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Manservisi et al., 2019

Manservisi, Fabiana, Lesseur, Corina, Panzacchi, Simona, Mandrioli, Daniele, Falcioni, Laura, Bua, Luciano, Manservigi, Marco, Spinaci, Marcella, Galeati, Giovanna, Mantovani, Alberto, Lorenzetti, Stefano, Miglio, Rossella, Andrade, Anderson Martino, Kristensen, David Møbjerg, Perry, Melissa J., Swan, Shanna H., Chen, Jia, & Belpoggi, Fiorella. “The Ramazzini Institute 13-week pilot study glyphosate-based herbicides administered at human-equivalent dose to Sprague Dawley rats: effects on development and endocrine system,” Environmental Health, 2019, 18(1). DOI:10.1186/s12940-019-0453-y.

ABSTRACT:

BACKGROUND: Glyphosate-based herbicides (GBHs) are broad-spectrum herbicides that act on the shikimate pathway in bacteria, fungi, and plants. The possible effects of GBHs on human health are the subject of an intense public debate for both its potential carcinogenic and non-carcinogenic effects, including potential effects on the endocrine system The present pilot study examine whether exposure to GBHs at the dose of glyphosate considered to be “safe” (the US Acceptable Daily Intake – ADI – of 1.75 mg/kg bw/day), starting from in utero life, affect the development and endocrine system across different life stages in Sprague Dawley (SD) rats.

METHODS: Glyphosate alone and Roundup Bioflow, a commercial brand of GBHs, were administered in drinking water at 1.75 mg/kg bw/day to F0 dams starting from the gestational day (GD) 6 (in utero) up to postnatal day (PND) 120. After weaning, offspring were randomly distributed in two cohorts: 8 M + 8F/group animals belonging to the 6-week cohort were sacrificed after puberty at PND 73 ± 2; 10 M + 10F/group animals belonging to the 13-week cohort were sacrificed at adulthood at PND 125 ± 2. Effects of glyphosate or Roundup exposure were assessed on developmental landmarks and sexual characteristics of pups.

RESULTS: In pups, anogenital distance (AGD) at PND 4 was statistically significantly increased both in Roundup treated males and females and in glyphosate-treated males. Age at first estrous (FE) was significantly delayed in the Roundup-exposed group and serum testosterone concentration significantly increased in Roundup-treated female offspring from the 13-week cohort compared to control animals. A statistically significant increase in plasma TSH concentration was observed in glyphosate-treated males compared with control animals as well as a statistically significant decrease in DHT and increase in BDNF in Roundup-treated males. Hormonal status imbalances were more pronounced in Roundup-treated rats after prolonged exposure.

CONCLUSIONS: The present pilot study demonstrate that GBHs exposure, from prenatal period to adulthood, induced endocrine effects and altered reproductive developmental parameters in male and female SD rats. In particular, it was associated with androgen-like effects, including a statistically significant increase of AGDs in both males and females, delay of FE and increased testosterone in female. FULL TEXT

Bell et al., 2006

Bell, E.M., Sandler, D. P., & Alavanja, M. C., “High Pesticide Exposure Events Among Farmers and Spouses Enrolled in the Agricultural Health Study.” Journal of Agricultural Safety and Health, 2006, 12(2), 101-116.

ABSTRACT:

We completed a nested case-control analysis of factors associated with reporting a high pesticide exposure event (HPEE) by pesticide applicators and spouses during the five years since enrollment in the Agricultural Health Study (AHS). Cases and controls were identified from the 16,415 private pesticide applicators and 14,045 spouses with completed five-year follow-up interviews as of October 2000. Among the applicators, 306 cases with at least one HPEE in the five years since enrollment and 612 controls, randomly selected from those without a reported HPEE, were identified for analysis. Among the spouses, 63 cases were identified and 126 controls were selected. Risk for a new HPEE was increased among applicators reporting at enrollment ever having an HPEE with an odds ratio (OR) of 3.8 (95% CI: 2.7, 5.3). Compared to applicators who applied pesticides fewer than 5 days per year, the ORs ranged from 1.4 (95% CI: 0.9, 2.2) for 6 to 10 days per year to 2.2 (95% CI: 1.4, 3.6) for more than 20 application days per year. The incidence of HPEE among Iowa applicators was much greater (8.8/1000 applicators) than among North Carolina applicators (2.0/1000). Spouses reported fewer HPEEs compared to applicators (2/1000 spouses). Overall, the observed risk factors for new HPEEs among applicators are similar to risk factors observed in previous cross-sectional analyses of HPEE history. Further, only 13% of applicators and 22% of spouses with symptoms resulting from HPEE sought medical care, suggesting that pesticide poisoning surveillance data may seriously underreport the frequency of such events.  FULL TEXT

Payne et al., 2012

Payne, K, Andreotti, G., Bell, E., Blair, A., Coble, J., & Alavanja, M., “Determinants of high pesticide exposure events in the agricultural health cohort study from enrollment (1993-1997) through phase II (1999-2003),” Journal of Agricultural Safety and Health, 2012, 18(3), 167-179.

ABSTRACT:

We conducted an analysis of the determinants of high pesticide exposure events (HPEEs), which are defined as self-reported incidents of high exposure to pesticides, fertilizers, or other chemicals in the Agricultural Health Study, a cohort of private applicators and their spouses residing in North Carolina or Iowa, and commercial applicators residing in Iowa. We examined the risk of HPEEs occurring between enrollment (phase 1: 1993-1997) and follow-up (phase II: 1999-2003) among participants who completed the phase II questionnaire (n=43,149) by calculating hazard rate ratios and 95% confidence intervals using Cox proportional-hazard regression. During the followup period, 1,582 HPEEs were reported (3.8%). HPEE risk was significantly higher among Iowa residents, younger participants, those with a hearing deficit, a risk-taking personality, and an HPEE prior to enrollment. Among private applicators (n=30,102), larger farm size, higher frequency and duration of pesticide use, spraying pesticides with open cab windows, using a tractor cab without a charcoal filter, repairing spray equipment, wearing work clothing more than two days without changing, not removing work boots before entering the home, and storing pesticides in the home were associated with significantly higher HPEE risk. Among commercial applicators (n=2326), higher frequency of pesticide use was associated with a significantly higher HPEE risk. Among spouses (n=10,721), higher frequency of pesticide use, using an application vehicle with a cab, and storing pesticides in the home were associated with a significantly higher HPEE risk. Our findings indicate that HPEEs were associated with several modifiable pesticide handling procedures that can be targeted in safety training and education. FULL TEXT

Cocco et al., 2013

Cocco, Pierluigi, Satta, Giannina, Dubois, Stefania, Pili, Claudia, Pilleri, Michela, Zucca, Mariagrazia, ‘t Mannetje, Andrea Martine, Becker, Nikolaus, Benavente, Yolanda, de Sanjosé, Silvia, Foretova, Lenka, Staines, Anthony, Maynadié, Marc, Nieters, Alexandra, Brennan, Paul, Miligi, Lucia, Ennas, Maria Grazia, & Boffetta, Paolo, “Lymphoma risk and occupational exposure to pesticides: results of the EPILYMPH study,” Occupational and Environmental Medicine, 2013, 70(2), 91, DOI: 10.1136/oemed-2012-100845.

ABSTRACT:

OBJECTIVES: We investigated the role of occupational exposure to specific groups of agrochemicals in the aetiology of lymphoma overall, B cell lymphoma and its most prevalent subtypes.

METHODS: In 1998–2003, 2348 incident lymphoma cases and 2462 controls were recruited to the EPILYMPH case-control study in six European countries. A detailed occupational history was collected in cases and controls. Job modules were applied for farm work including specific questions on type of crop, farm size, pests being treated, type and schedule of pesticide use. In each study centre, industrial hygienists and occupational experts assessed exposure to specific groups of pesticides and individual compounds with the aid of agronomists. We calculated the OR and its 95% CI associated with lymphoma and the most prevalent lymphoma subtypes with unconditional logistic regression, adjusting for age, gender, education and centre.

RESULTS: Risk of lymphoma overall, and B cell lymphoma was not elevated, and risk of chronic lymphocytic leukaemia (CLL) was elevated amongst those ever exposed to inorganic (OR=1.6, 95% CI 1.0 to 2.5) and organic pesticides (OR=1.5, 95% CI 1.0 to 2.1). CLL risk was highest amongst those ever exposed to organophosphates (OR=2.7, 95% CI 1.2 to 6.0). Restricting the analysis to subjects most likely exposed, no association was observed between pesticide use and risk of B cell lymphoma.

CONCLUSIONS: Our results provide limited support to the hypothesis of an increase in risk of specific lymphoma subtypes associated with exposure to pesticides. FULL TEXT

Hohenadel et al., 2011

Hohenadel, Karin, Harris, Shelley A, McLaughlin, John R, Spinelli, John J, Pahwa, Punam, Dosman, James A, Demers, Paul A, & Blair, Aaron., “Exposure to multiple pesticides and risk of non-Hodgkin lymphoma in men from six Canadian provinces,” International Journal of Environmental Research and Public Health, 2011, 8(6), 2320-2330. doi:10.3390/ijerph8062320.

ABSTRACT:

Non-Hodgkin lymphoma (NHL) has been linked to several agricultural exposures, including some commonly used pesticides. Although there is a significant body of literature examining the effects of exposure to individual pesticides on NHL, the impact of exposure to multiple pesticides or specific pesticide combinations has not been explored in depth. Data from a six-province Canadian case-control study conducted between 1991 and 1994 were analyzed to investigate the relationship between NHL, the total number of pesticides used and some common pesticide combinations. Cases (n=513) were identified through hospital records and provincial cancer registries and controls (n=1,506), frequency matched to cases by age and province of residence, were obtained through provincial health records, telephone listings, or voter lists. In multiple logistic regression analyses, risk of NHL increased with the number of pesticides used. Similar results were obtained in analyses restricted to herbicides, insecticides and several pesticide classes. Odds ratios increased further when only ‘potentially carcinogenic’ pesticides were considered (OR[one pesticide]=1.30, 95% CI=0.90-1.88; OR[two to four]=1.54, CI=1.11-2.12; OR[five or more]=1.94, CI=1.17-3.23). Elevated risks were also found among those reporting use of malathion in combination with several other pesticides. These analyses support and extend previous findings that the risk of NHL increases with the number of pesticides used and some pesticide combinations. FULL TEXT

Wijkstrom et al., 2018

Wijkstrom, Julia; Jayasumana, Channa; Dassanayake, Rajeewa; Priyawardane, Nalin; Godakanda, Nimali; Siribaddana, Sisira; Ring, Anneli; Hultenby, Kjell
Soderberg, Magnus; Elinder, Carl-Gustaf; Wernerson, Annika, “Morphological and clinical findings in Sri Lankan patients with chronic kidney disease of unknown cause (CKDu): Similarities and differences with Mesoamerican Nephropathy, PLoS One, 2018, 13:3, DOI:10.1371/journal.pone.0193056.

ABSTRACT:

In Sri Lanka, an endemic of chronic kidney disease of unknown origin (CKDu) is affecting rural communities. The endemic has similarities with Mesoamerican Nephropathy (MeN) in Central America, however it has not yet been clarified if the endemics are related diagnostic entities. We designed this study of kidney biopsies from patients with CKDu in Sri Lanka to compare with MeN morphology. Eleven patients with CKDu were recruited at the General Hospital, Polonnaruwa, using similar inclusion and exclusion criteria as our previous MeN studies. Inclusion criteria were 20-65 years of age and plasma creatinine 100-220 mumol/L. Exclusion criteria were diabetes mellitus, uncontrolled hypertension and albuminuria >1g/24h. Kidney biopsies, blood and urine samples were collected, and participants answered a questionnaire. Included participants were between 27-61 years of age and had a mean eGFR of 38+/-14 ml/min/1.73m2. Main findings in the biopsies were chronic glomerular and tubulointerstitial damage with glomerulosclerosis (8-75%), glomerular hypertrophy and mild to moderate tubulointerstitial changes. The morphology was more heterogeneous and interstitial inflammation and vascular changes were more common compared to our previous studies of MeN. In two patients the biopsies showed morphological signs of acute pyelonephritis but urine cultures were negative. Electrolyte disturbances with low levels of serum sodium, potassium, and/or magnesium were common. In the urine, only four patients displayed albuminuria, but many patients exhibited elevated alpha-1-microglobulin and magnesium levels. This is the first study reporting detailed biochemical and clinical data together with renal morphology, including electron microscopy, from Sri Lankan patients with CKDu. Our data show that there are many similarities in the biochemical and morphological profile of the CKDu endemics in Central America and Sri Lanka, supporting a common etiology. However, there are differences, such as a more mixed morphology, more interstitial inflammation and vascular changes in Sri Lankan patients. FULL TEXT

Connolly et al., 2018

Connolly A, Jones K, Basinas I, Galea KS, Kenny L, McGowan P, Coggins MA, “Exploring the half-life of glyphosate in human urine samples,” International Journal of Hygeine and Environmental Health, 2018 (EPub), doi:10.1016/j.ijheh.2018.09.004.

ABSTRACT:

BACKGROUND: The International Agency for Research on Cancer (IARC) has recently classified glyphosate as a Group 2A ‘probably carcinogenic to humans’. Due to this carcinogenic classification and resulting international debate, there is an increased demand for studies evaluating human health effects from glyphosate exposures. There is currently limited information on human exposures to glyphosate and a paucity of data regarding glyphosate’s biological half-life in humans.

OBJECTIVE: This study aims to estimate the human half-life of glyphosate from human urine samples collected from amenity horticulture workers using glyphosate based pesticide products.

METHODS: Full void urine spot samples were collected over a period of approximately 24 h for eight work tasks involving seven workers. The elimination time and estimation of the half-life of glyphosate using three different measurement metrics: the unadjusted glyphosate concentrations, creatinine corrected concentrations and by using Urinary Excretion Rates (UER) (μgL−1, μmol/mol creatinine and UER μgL−1) was calculated by summary and linear interpolation using regression analysis.

RESULTS: This study estimates the human biological half-life of glyphosate as approximately 5 ½, 10 and 7 ¼ hours for unadjusted samples, creatinine corrected concentrations and by using UER (μgL−1, μmol/mol creatinine, UER μgL−1), respectively. The approximated glyphosate half-life calculations seem to have less variability when using the UER compared to the other measuring metrics.

CONCLUSION: This study provides new information on the elimination rate of glyphosate and an approximate biological half-life range for humans. This information can help optimise the design of sampling strategies, as well as assisting in the interpretation of results for human biomonitoring studies involving this active ingredient. The data could also contribute to the development or refinement of Physiologically Based PharmacoKinetic (PBPK) models for glyphosate. FULL TEXT

 

Jayasumana, 2015b

Jayasumana C, Paranagama P, Agampodi S, Wijewardane C, Gunatilake S, Siribaddana S, “Drinking well water and occupational exposure to Herbicides is associated with chronic kidney disease in Padavi-Sripura, Sri Lanka,” 2015, Environmental Health, 14:6, DOI:10.1186/1476-069X-14-6.

ABSTRACT:

BACKGROUND: The chronic kidney disease of unknown etiology (CKDu) among paddy farmers in was first reported in 1994 and has now become most important public health issue in dry zone of Sri Lanka. The objective was to identify risk factors associated with the epidemic in an area with high prevalence.

METHODS: A case control study was carried out in Padavi-Sripura hospital in Trincomalee district. CKDu patients were defined using health ministry criteria. All confirmed cases (N = 125) fulfilling the entry criteria were recruited to the study. Control selection (N = 180) was done from people visiting the hospital for CKDu screening. Socio-demographic and data related to usage of applying pesticides and fertilizers were studied. Drinking water was also analyzed using ICP-MS and ELISA to determine the levels of metals and glyphosate.

RESULTS: Majority of patients were farmers (N = 107, 85.6%) and were educated up to ‘Ordinary Level’ (N = 92, 73.6%). We specifically analyzed for the effect modification of, farming by sex, which showed a significantly higher risk for male farmers with OR 4.69 (95% CI 1.06-20.69) in comparison to their female counterparts. In the multivariable analysis the highest risk for CKDu was observed among participants who drank well water (OR 2.52, 95% CI 1.12-5.70) and had history of drinking water from an abandoned well (OR 5.43, 95% CI 2.88-10.26) and spray glyphosate (OR 5.12, 95% CI 2.33-11.26) as a pesticide. Water analysis showed significantly higher amount of hardness, electrical conductivity and glyphosate levels in abandoned wells. In addition Ca, Mg, Ba, Sr, Fe, Ti, V and Sr were high in abandoned wells. Surface water from reservoirs in the endemic area also showed contamination with glyphosate but at a much lower level. Glyphosate was not seen in water samples in the Colombo district.

CONCLUSION: The current study strongly favors the hypothesis that CKDu epidemic among farmers in dry zone of Sri Lanka is associated with, history of drinking water from a well that was abandoned. In addition, it is associated with spraying glyphosate and other pesticides in paddy fields. Farmers do not use personnel protective equipments and wears scanty clothing due to heat when spraying pesticides. FULL TEXT

Bradman et al., 2013

Bradman, Asa; Kogut, Katherine; Eisen, Ellen A; Jewell, Nicholas P; Quiros-Alcala, Lesliam; Castorina, Rosemary; Chevrier, Jonathan; Holland, Nina T;  Barr, Dana Boyd; Kavanagh-Baird, Geri; Eskenazi, Brenda, “Variability of organophosphorous pesticide metabolite levels in spot and 24-hr urine samples collected from young children during 1 week,” Environmental Health Perspectives, 2013, 121:118-124. DOI:10.1289/ehp.1104808.

ABSTRACT:

BACKGROUND: Dialkyl phosphate (DAP) metabolites in spot urine samples are frequently used to characterize children’s exposures to organophosphorous (OP) pesticides. However, variable exposure and short biological half-lives of OP pesticides could result in highly variable measurements, leading to exposure misclassification.

OBJECTIVE: We examined within- and between-child variability in DAP metabolites in urine samples collected during 1 week.

METHODS: We collected spot urine samples over 7 consecutive days from 25 children (3-6 years of age). On two of the days, we collected 24-hr voids. We assessed the reproducibility of urinary DAP metabolite concentrations and evaluated the sensitivity and specificity of spot urine samples as predictors of high (top 20%) or elevated (top 40%) weekly average DAP metabolite concentrations.

RESULTS: Within-child variance exceeded between-child variance by a factor of two to eight, depending on metabolite grouping. Although total DAP concentrations in single spot urine samples were moderately to strongly associated with concentrations in same-day 24-hr samples (r approximately 0.6-0.8, p < 0.01), concentrations in spot samples collected > 1 day apart and in 24-hr samples collected 3 days apart were weakly correlated (r approximately -0.21 to 0.38). Single spot samples predicted high (top 20%) and elevated (top 40%) full-week average total DAP excretion with only moderate sensitivity ( approximately 0.52 and approximately 0.67, respectively) but relatively high specificity ( approximately 0.88 and approximately 0.78, respectively).

CONCLUSIONS: The high variability we observed in children’s DAP metabolite concentrations suggests that single-day urine samples provide only a brief snapshot of exposure. Sensitivity analyses suggest that classification of cumulative OP exposure based on spot samples is prone to type 2 classification errors.  FULL TEXT

Bradman et al., 2003

Bradman A, Barr DB, Claus Henn BG, Drumheller T, Curry C, Eskenazi B, “Measurement of pesticides and other toxicants in amniotic fluid as a potential biomarker of prenatal exposure: a validation study,” Environmental Health Perspectives, 2003, 111:1779-1782. DOI:10.1289/ehp.6259.

ABSTRACT:

Prenatal pesticide exposures may adversely affect children’s health. However, exposure and health research is hampered by the lack of reliable fetal exposure data. No studies have been published that report measurements of commonly used nonpersistent pesticides in human amniotic fluid, although recent studies of pesticides in urine from pregnant women and in meconium indicate that fetuses are exposed to these chemicals. Amniotic fluid collected during amniocentesis is the only medium available to characterize direct fetal exposures early in pregnancy (approximately 18 weeks of gestation). As a first step in validating this exposure biomarker, we collected 100 amniotic fluid samples slated for disposal and evaluated analytical methods to measure organophosphate and carbamate pesticides and metabolites, synthetic pyrethroid metabolites, herbicides, and chlorinated phenolic compounds. The following six phenols were detected (detection frequency): 1- and 2-naphthol (70%), 2,5-dichlorophenol (55%), carbofuranphenol (5%), ortho-phenylphenol (30%), and pentachlorophenol (15%), with geometric mean concentrations of 0.72, 0.39, 0.12, 0.13, and 0.23 microg/L, respectively, for positive values. The organophosphate metabolites diethylphosphate and dimethylphosphate were detected in two (10%) samples, and dimethylthiophosphate was detected in one (5%) sample, with geometric mean concentrations of 0.31, 0.32, and 0.43 microg/L, respectively, for positive values. These levels are low compared with levels reported in urine, blood, and meconium in other studies, but indicate direct exposures to the young fetus, possibly during critical periods of development. Results of this pilot study suggest that amniotic fluid offers a unique opportunity to investigate fetal exposures and health risks.  FULL TEXT

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