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Bibliography Tag: birth defects

Weselak et al., 2007

Weselak M, Arbuckle TE, Foster W., “Pesticide exposures and developmental outcomes: the epidemiological evidence.,” Journal of Toxicology and Environmental Health, Part B, Critical Reviews, 1-2, 2007,  DOI: 10.1080/10937400601034571


Since the advent of DDT as an insecticide in the late 1930s, billions of kilograms of pesticide active ingredient have been sold in North America and around the world. In recent years, there has been a heightened public awareness of pesticides and child health and a number of epidemiologic studies linked pre- and postnatal exposures to pesticides to a number of adverse developmental outcomes, including fetal death, intrauterine growth restriction, preterm birth, and birth defects. Given this, it was felt prudent to critically appraise the evidence for periconceptual pesticide exposures and developmental outcomes. The epidemiological evidence for specific pesticide classes, families, and active ingredients were examined and summarized and recommendations were made for how to improve future studies in order to address the current pitfalls and gaps in the studies in this area. Many of the studies suffered from poor exposure estimation, relying on job title only and/or the exposure category “any pesticide” as a measure of exposure, and there was limited or inadequate evidence to support causality for all associations examined.

Rull et al., 2006

Rudolph P. Rull Beate Ritz Gary M. Shaw, “Neural Tube Defects and Maternal Residential Proximity to Agricultural Pesticide Applications,” American Journal of Epidemiology, 163:8, 15 April 2006, DOI: 10.1093/aje/kwj101


Residential proximity to applications of agricultural pesticides may be an important source of exposure to agents that have been classified as developmental toxins. Data on two case-control study populations of infants with neural tube defects (NTDs) and nonmalformed controls delivered in California between 1987 and 1991 were pooled to investigate whether maternal residential proximity to applications of specific pesticides or physicochemical groups of pesticides during early gestation increases the risk of these malformations. Maternal residential proximity within 1,000 m of pesticide applications was ascertained by linking mothers’ addresses with agricultural pesticide use reports and crop maps. Odds ratios were computed by using conventional single- and multiplepesticide and hierarchical multiple-pesticide logistic regression. In single-pesticide models, several pesticides were associated with NTDs after adjustment for study population, maternal ethnicity, educational level, cigarette smoking, and vitamin use. In a hierarchical multiple-pesticide model, effect estimates for only benomyl and methomyl suggested a possible association. Elevated risks of NTDs and anencephaly or spina bifida subtypes were also  associated with exposures to chemicals classified as amide, benzimidazole, methyl carbamate, or organophosphorus pesticides and with increasing numbers of pesticides. These results suggest that ambient exposure to certain categories of agricultural pesticides may increase the risk of NTDs.  FULL TEXT

Benachour et al., 2007

N. Benachour, H. Sipahutar, S. Moslemi, C. Gasnier, C. Travert, G. E. Séralini, “Time- and Dose-Dependent Effects of Roundup on Human Embryonic and Placental Cells,” Archives of Environmental Contamination and Toxicology, 53:1, July 2007, DOI:


Roundup® is the major herbicide used worldwide, in particular on genetically modified plants that have been designed to tolerate it. We have tested the toxicity and endocrine disruption potential of Roundup (Bioforce®) on human embryonic 293 and placental-derived JEG3 cells, but also on normal human placenta and equine testis. The cell lines have proven to be suitable to estimate hormonal activity and toxicity of pollutants. The median lethal dose (LD50) of Roundup with embryonic cells is 0.3% within 1 h in serum-free medium, and it decreases to reach 0.06% (containing among other compounds 1.27 mM glyphosate) after 72 h in the presence of serum. In these conditions, the embryonic cells appear to be 2–4 times more sensitive than the placental ones. In all instances, Roundup (generally used in agriculture at 1–2%, i.e., with 21–42 mM glyphosate) is more efficient than its active ingredient, glyphosate, suggesting a synergistic effect provoked by the adjuvants present in Roundup. We demonstrated that serum-free cultures, even on a short-term basis (1 h), reveal the xenobiotic impacts that are visible 1–2 days later in serum. We also document at lower non-overtly toxic doses, from 0.01% (with 210 μM glyphosate) in 24 h, that Roundup is an aromatase disruptor. The direct inhibition is temperature-dependent and is confirmed in different tissues and species (cell lines from placenta or embryonic kidney, equine testicular, or human fresh placental extracts). Furthermore, glyphosate acts directly as a partial inactivator on microsomal aromatase, independently of its acidity, and in a dose-dependent manner. The cytotoxic, and potentially endocrine-disrupting effects of Roundup are thus amplified with time. Taken together, these data suggest that Roundup exposure may affect human reproduction and fetal development in case of contamination. Chemical mixtures in formulations appear to be underestimated regarding their toxic or hormonal impact. FULL TEXT


Dallegrave et al., 2003

Eliane Dallegrave, Fabiana DiGiorgio Mantese, Ricardo Soares Coelho, Janaı´na Drawans Pereira, Paulo Roberto Dalsenter, Augusto Langeloh, “The teratogenic potential of the herbicide glyphosate-Roundup in Wistar rats,” Toxicology Letters, 142, 2003, DOI: 10.1016/S0378-4274(02)00483-6.


The aim of this study was to assess the teratogenicity of the herbicide glyphosate-Roundup† (as commercialized in Brazil) to Wistar rats. Dams were treated orally with water or 500, 750 or 1000 mg/kg glyphosate from day 6 to 15 of pregnancy. Cesarean sections were performed on day 21 of pregnancy, and number of corpora lutea, implantation sites, living and dead fetuses, and resorptions were recorded. Weight and gender of the fetuses were determined, and fetuses
were examined for external malformations and skeletal alterations. The organs of the dams were removed and weighed. Results showed a 50% mortality rate for dams treated with 1000 mg/kg glyphosate. Skeletal alterations were observed in 15.4, 33.1, 42.0 and 57.3% of fetuses from the control, 500, 750 and 1000 mg/kg glyphosate groups, respectively. We may conclude that glyphosate-Roundup† is toxic to the dams and induces developmental retardation of the fetal
skeleton.  FULL TEXT

Robinson et al., 2012

CJ Robinson, M Antoniou, MEM Habib,  CV Howard, RC Jennings, C Leifert, RO Nodari, and J Fagan, “Teratogenic Effects of Glyphosate-Based Herbicides: Divergence of Regulatory Decisions from Scientific Evidence,” Environmental and Analytical Toxicology, S:4, 2012, DOI: 10.4172/2161-0525.S4-006.


The publication of a study in 2010, showing that a glyphosate herbicide formulation and glyphosate alone caused malformations in the embryos of Xenopus laevis and chickens through disruption of the retinoic acid signalling pathway, caused scientific and regulatory controversy. Debate centred on the effects of the production and consumption of genetically modified Roundup Ready® soy, which is engineered to tolerate applications of glyphosate herbicide. The study, along with others indicating teratogenic and reproductive effects from glyphosate herbicide exposure, was rebutted by the German Federal Office for Consumer Protection and Food Safety, BVL, as well as in industry-sponsored papers. These rebuttals relied partly on unpublished industry-sponsored studies commissioned for regulatory purposes, which, it was claimed, showed that glyphosate is not a teratogen or reproductive toxin.

However, examination of the German authorities’ draft assessment report on the industry studies, which underlies glyphosate’s EU authorisation, revealed further evidence of glyphosate’s teratogenicity. Many of the malformations found were of the type defined in the scientific literature as associated with retinoic acid teratogenesis. Nevertheless, the German and EU authorities minimized these findings in their assessment and set a potentially unsafe acceptable daily intake (ADI) level for glyphosate. This paper reviews the evidence on the teratogenicity and reproductive toxicity of glyphosate herbicides and concludes that a new and transparent risk assessment needs to be conducted. The new risk assessment must take into account all the data on the toxicity of glyphosate and its commercial formulations, including data generated by independent scientists and published in the peer-reviewed scientific literature, as well as the industry-sponsored studies.  FULL TEXT

Paganelli et al., 2010

Alejandra Paganelli, Victoria Gnazzo, Helena Acosta, Silvia L. López, and Andrés E. Carrasco, “Glyphosate-Based Herbicides Produce Teratogenic Effects on Vertebrates by Impairing Retinoic Acid Signaling,” Chemical Research in Toxicology, 2010, 23:10, DOI: 10.1021/TX1001749.


The broad spectrum herbicide glyphosate is widely used in agriculture worldwide. There has been ongoing controversy regarding the possible adverse effects of glyphosate on the environment and on human health. Reports of neural defects and craniofacial malformations from regions where glyphosate-based herbicides (GBH) are used led us to undertake an embryological approach to explore the effects of low doses of glyphosate in development. Xenopus laevis embryos were incubated with 1/5000 dilutions of a commercial GBH. The treated embryos were highly abnormal with marked alterations in cephalic and neural crest development and shortening of the anterior−posterior (A-P) axis. Alterations on neural crest markers were later correlated with deformities in the cranial cartilages at tadpole stages. Embryos injected with pure glyphosate showed very similar phenotypes. Moreover, GBH produced similar effects in chicken embryos, showing a gradual loss of rhombomere domains, reduction of the optic vesicles, and microcephaly. This suggests that glyphosate itself was responsible for the phenotypes observed, rather than a surfactant or other component of the commercial formulation. A reporter gene assay revealed that GBH treatment increased endogenous retinoic acid (RA) activity in Xenopus embryos and cotreatment with a RA antagonist rescued the teratogenic effects of the GBH. Therefore, we conclude that the phenotypes produced by GBH are mainly a consequence of the increase of endogenous retinoid activity. This is consistent with the decrease of Sonic hedgehog (Shh) signaling from the embryonic dorsal midline, with the inhibition of otx2 expression and with the disruption of cephalic neural crest development. The direct effect of glyphosate on early mechanisms of morphogenesis in vertebrate embryos opens concerns about the clinical findings from human offspring in populations exposed to GBH in agricultural fields.  FULL TEXT


Markel et al., 2015

Markel TA, Proctor C, Ying J, Winchester PD, “Environmental pesticides increase the risk of developing hypertrophic pyloric stenosis,” Journal of Pediatric Surgery, 2015, 50:8, DOI: 10.1016/J.JPEDSURG.2014.12.009.


BACKGROUND: Hypertrophic pyloric stenosis (HPS) is a condition noted within the first several weeks of life that results in hypertrophy of the pyloric muscle between the stomach and duodenum. The etiology has not been elucidated but genetic and environmental influences are suspected. We hypothesized that agricultural pesticides would be associated with an increased incidence of pyloric stenosis.

STUDY DESIGN: Data from infants with HPS were obtained from the Indiana Birth Defects Registry (IBDR) for all counties in Indiana from 2005 to 2009. Data from all live births were obtained from the Indiana State Health Department (ISHD). Maternal demographics and clinical characteristics of infants were abstracted. The US Geological Survey (USGS) provided estimated use of agricultural pesticides (EPEST), and these values were correlated with HPS incidence. Univariate and multivariate logistical regression models were used to assess the association between HPS risk and pesticide use.

RESULTS: A total of 442,329 newborns were studied with 1313 HPS cases recorded. The incidence of HPS was 30/10,000 live births. HPS incidence was correlated with total county pesticide use, as well as subcategories of pesticides (fungicides, fumigants, insecticides, herbicides). Indiana counties were then divided into low, moderate and high pesticide use (mean±standard deviation: 127,722±73,374, 308,401±36,915, and 482,008±97,260pounds of pesticides). Incidence of HPS was 26, 29, and 36 cases per 10,000 in low, moderate and high pesticide-use counties respectively. Subset analysis showed that the positive association between HPS and county pesticide use was more likely for male infants from mothers who were white, aged 20-35 years, had education at high school or lower, and smoked (p<0.05).

CONCLUSION: Pesticide use correlated significantly with incidence of HPS. Positive correlations between HPS risk and pesticide use were found for most risk factors. Further studies will be needed to verify our findings and further delineate the nature of this correlation.

Sisto et al., 2015

Renata Sisto, Arturo Moleti, L’ubica Palkovičová Murínová, Soňa Wimmerová, Kinga Lancz, Juraj Tihányi, Kamil Čonka, Eva Šovčíková, Irva Hertz-Picciotto, Todd A. Jusko, and Tomáš Trnovec, “Environmental exposure to organochlorine pesticides and deficits in cochlear status in children,” Environmental Science and Pollution Research, 2015, 22:19, DOI: 10.107/S11356-015-489-5.


The aim of this study was to examine the hypothesis that organochlorine pesticides (OCPs), hexachlorobenzene (HCB), β-hexachlorocyclohexane (β-HCH), 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (p,p′-DDT) and its metabolite 1,1-dichloro-2,2-bis(4-chlorophenyl)ethylene (p,p′-DDE) are ototoxic to humans. A Multivariate General Linear Model was designed, in which the statistical relation between blood serum concentrations of HCB, β-HCH, p,p′-DDT or p,p′-DDE at the different ages (at birth, 6, 16 and 45 months) and the DPOAEs were treated as multivariate outcome variables. PCB congeners and OCPs were strongly correlated in serum of children from our cohort. To ascertain that the association between DPOAEs at a given frequency and concentration of a pesticide is not influenced by PCBs or other OCP also present in serum, we calculated BMCs relating DPOAEs to a serum pesticides alone and in presence of confounding PCB-153 or other OCPs. We found that BMCs relating DPOAEs to serum pesticides are not affected by confounders. DPOAE amplitudes were associated with serum OCPs at all investigated time intervals, however in a positive way with prenatal exposure and in a negative way with all postnatal exposures. We observed tonotopicity in the association of pesticides with amplitude of DPOAEs as its strength was frequency dependent. We conclude that exposure to OCPs in infancy at environmental concentrations may be associated with hearing deficits.  FULL TEXT

Cimino et al., 2017

Andria M. Cimino, Abee L. Boyles, Kristina A. Thayer, and Melissa J. Perry, “Effects of Neonicotinoid Pesticide Exposure on Human Health: A Systematic Review,” Environmental Health Perspectives, 2017, 125:2, DOI: 10.1289/EHP515.


BACKGROUND: Numerous studies have identified detectable levels of neonicotinoids (neonics) in the environment, adverse effects of neonics in many species, including mammals, and pathways through which human exposure to neonics could occur, yet little is known about the human health effects of neonic exposure.

OBJECTIVE: In this systematic review, we sought to identify human population studies on the health effects of neonics.

METHODS: Studies published in English between 2005 and 2015 were searched using PubMed, Scopus, and Web of Science databases. No restrictions were placed on the type of health outcome assessed. Risk of bias was assessed using guidance developed by the National Toxicology Program’s Office of Health Assessment and Translation.

RESULTS: Eight studies investigating the human health effects of exposure to neonics were identified. Four examined acute exposure: Three neonic poisoning studies reported two fatalities (n = 1,280 cases) and an occupational exposure study of 19 forestry workers reported no adverse effects. Four general population studies reported associations between chronic neonic exposure and adverse developmental or neurological outcomes, including tetralogy of Fallot (AOR 2.4, 95% CI: 1.1, 5.4), anencephaly (AOR 2.9, 95% CI: 1.0, 8.2), autism spectrum disorder [AOR 1.3, 95% credible interval (CrI): 0.78, 2.2], and a symptom cluster including memory loss and finger tremor (OR 14, 95% CI: 3.5, 57). Reported odds ratios were based on exposed compared to unexposed groups.

CONCLUSIONS: The studies conducted to date were limited in number with suggestive but methodologically weak findings related to chronic exposure. Given the wide-scale use of neonics, more studies are needed to fully understand their effects on human health.  FULL TEXT

Chevrier et al., 2011

Cecile Chevrier, Gwendolina Limon, Christine Monfort, Florence Rouget, Ronan Garlantezec, et al., “Urinary biomarkers of prenatal atrazine exposure and adverse birth outcomes in the PELAGIE birth cohort,” Environmental Health Perspectives, 2011, 119:7, DOI: 10.1289/EHP.100277.


BACKGROUND:  Despite evidence of atrazine toxicity in developing organisms from experimental studies, few studies—and fewer epidemiologic investigations—have examined the potential effects of prenatal exposure.

OBJECTIVES: We assessed the association between adverse birth outcomes and urinary biomarkers of prenatal atrazine exposure, while taking into account exposures to other herbicides used on corn crops (simazine, alachlor, metolachlor, and acetochlor).

METHODS: This study used a case-cohort design nested in a prospective birth cohort conducted in the Brittany region of France from 2002 through 2006. We collected maternal urine samples to examine pesticide exposure biomarkers before the 19th week of gestation.

RESULTS: We found quantifiable levels of atrazine or atrazine mercapturate in urine samples from 5.5% of 579 pregnant women, and dealkylated and identified hydroxylated triazine metabolites in 20% and 40% of samples, respectively. The presence versus absence of quantifiable levels of atrazine or a specific atrazine metabolite was associated with fetal growth restriction [odds ratio (OR) = 1.5; 95% confidence interval (CI), 1.0–2.2] and small head circumference for sex and gestational age (OR = 1.7; 95% CI, 1.0–2.7). Associations with major congenital anomalies were not evident with atrazine or its specific metabolites. Head circumference was inversely associated with the presence of quantifiable urinary metolachlor.

CONCLUSIONS: This study is the first to assess associations of birth outcomes with multiple urinary biomarkers of exposure to triazine and chloroacetanilide herbicides. Evidence of associations with adverse birth outcomes raises particular concerns for countries where atrazine is still in use.  FULL TEXT

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