Pesticide-Induced Diseases: Diabetes
According to the American Diabetes Association, diabetes is a group of diseases characterized by high blood glucose levels that result from defects in the body’s ability to produce and/or use insulin. Type 1 diabetes is usually diagnosed in children and young adults. In type 1 diabetes, the body does not produce insulin. Type 2 diabetes is the most common form of diabetes and is most common in communities of color and the aged population. In type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. Pesticides and other environmental factors are almost always linked to type 2 diabetes.
- High levels of organochlorine pesticides in drinking water as a risk factor for type 2 diabetes: A study in north India
Organochlorine pesticides (OCPs) are well known synthetic pesticides widely used in agricultural practices and public health program. Higher toxicity, slow degradation, and bioaccumulation are the significant challenges of OCPs. Due to its uses in agricultural and public health, contamination of drinking water and water table also increases day by day. Contaminated drinking water has become a significant issue and alarming signal for public health globally. The purpose of this study was to assess the recent trend of organochlorine pesticides (OCPs) level in drinking water and blood samples of the North Indian population and also to find out its association with glucose intolerance, lipid metabolism, and insulin resistance, which are known risk factors of type 2 diabetes mellitus (T2DM). A case-control study was conducted on 130 Non-Glucose intolerance (NGT), 130 pre-diabetes and 130 recently diagnosed T2DM subjects of the age group of 30-70 years. Patients consuming drinking water from the same source for at least ten years were included in this study for blood and water samples collection. Significantly higher levels of α-HCH, β-HCH, γ-HCH, p,p'-DDE, and o,p'-DDT were found in groundwater samples. However, in tap water samples, the level of α-HCH was found to be slightly higher than the permissible limit of 0.001. Among all recruited subjects consuming contaminated groundwater, 42% had T2DM, 38% pre-diabetes, and the remaining 20% were found normal. We also observed that OCP contamination in groundwater is higher than tap and filter water. The levels of β-HCH, p,p'-DDE, and o,p'-DDT were higher in the pre-diabetes and T2DM group than the NGT group. With an increase of OCPs level in groundwater, the blood OCPs level tends to increase T2DM risk. It depicts that the elevated OCPs level in consumed groundwater may contribute to increased risk for the development of T2DM after a certain period of exposure.
[Tyagi, S., Siddarth, M., Mishra, B.K., Banerjee, B.D., Urfi, A.J. and Madhu, S.V., 2021. Environmental Pollution, 271, p.116287.]
- Longitudinal association of biomarkers of pesticide exposure with cardiovascular disease risk factors in youth with diabetes
Cardiovascular disease (CVD) is the leading cause of death among individuals with diabetes, but little is known about the role of exposures to environmental chemicals such as pesticides in the early development of CVD risk in this population. To describe changes over time in concentrations of pesticide biomarkers among youth with diabetes in the United States and to estimate the longitudinal association between these concentrations and established risk factors for CVD. Pesticide biomarkers were quantified in urine and serum samples from 87 youth with diabetes participating in the multi-center SEARCH cohort study. Samples were obtained around the time of diagnosis (baseline visit, between 2006 and 2010) and, on average, 5.4 years later (follow-up visit, between 2012 and 2015). We calculated geometric mean (95% CI) pesticide biomarker concentrations. Eight CVD risk factors were measured at these two time points: body mass index (BMI) z-score, HbA1c, insulin sensitivity, fasting C-peptide (FCP), LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides. Linear regression models were used to estimate the associations between each pesticide biomarker at baseline and each CVD risk factor at follow-up, adjusting for baseline health outcome, elapsed time between baseline and follow up, sex, age, race/ethnicity, and diabetes type. Participants were, on average, 14.2 years old at their baseline visit, and most were diagnosed with type 1 diabetes (57.5%). 4-nitrophenol, 3-phenoxybenzoic acid, 2,4-dichlorophenoxyacetic acid (2,4-D), 3,5,6-trichloro-2-pyridinol, 2,2-bis(4-chlorophenyl)-1,1-dichloroethene, and hexachlorobenzene were detected in a majority of participants at both time points. Participants in the highest quartile of 2,4-D and 4-nitrophenol at baseline had HbA1c levels at follow-up that were 1.05 percentage points (95% CI: −0.40, 2.51) and 1.27 percentage points (0.22, 2.75) higher, respectively, than participants in the lowest quartile of these pesticide biomarkers at baseline. These participants also had lower log FCP levels (indicating reduced beta-cell function) compared to participants in the lowest quartile at baseline: beta (95% CI) for log FCP of −0.64 (−1.17, −0.11) for 2,4-D and −0.39 (−0.96, 0.18) for 4-nitrophenol. In other words, participants in the highest quartile of 2,4-D had a 47.3% lower FCP level compared to participants in the lowest quartile, and those in the highest quartile of 4-nitrophenol had a 32.3% lower FCP level than those in the lowest quartile. Participants with trans-nonachlor concentrations in the highest quartile at baseline had HbA1c levels that were 1.45 percentage points (−0.11, 3.01) higher and log FCP levels that were −0.28 (−0.84, 0.28) lower than participants in the lowest quartile at baseline, that is to say, participants in the highest quartile of trans-nonachlor had a 24.4% lower FCP level than those in the lowest quartile. While not all of these results were statistically significant, potentially due to the small same size, clinically, there appears to be quantitative differences. No associations were observed between any pesticide biomarker at baseline with BMI z-score or insulin sensitivity at follow-up.Exposure to select pesticides may be associated with impaired beta-cell function and poorer glycemic control among youth with diabetes.
[Kaur, N., Starling, A.P., Calafat, A.M., Sjodin, A., Clouet-Foraison, N., Dolan, L.M., Imperatore, G., Jensen, E.T., Lawrence, J.M., Ospina, M. and Pihoker, C., 2020. Environmental Research, 181, p.108916.]
- Prospective association between organic food consumption and the risk of type 2 diabetes: findings from the NutriNet-Santé cohort study
Organic food (OF) consumption has substantially increased in high income countries, mostly driven by environmental concerns and health beliefs. Lower exposure to synthetic pesticides has been systematically documented among consumers of organic products compared to non-consumers. While experimental studies suggest that pesticides currently used in food production may be associated with type 2 diabetes (T2D), no well-conducted prospective studies have investigated the potential association between consumption of organic products and the risk of T2D, controlling for potential confounding factors. The objective of this prospective study was to estimate the association between OF consumption and the risk of T2D. A total of 33,256 participants (76% women, mean (SD) age: 53 years (14)) of the French NutriNet-Santé prospective cohort study who completed the organic food frequency questionnaire were included (2014–2019). The proportion of OF in the diet (as weight without drinking water) was computed. The associations between the proportion of OF in the diet (as 5% increment and as quintiles) and the risk of T2D were estimated using multivariable Hazard Ratio (HR) and 95% confidence interval (95% CI) derived from proportional hazards models adjusted for confounders (sociodemographic, anthropometric, lifestyle, medical and nutritional factors). During follow-up (mean = 4.05 y, SD = 1.03 y, 134,990 person-years), 293 incident cases of T2D were identified. After adjustment for confounders including lifestyle (physical activity, smoking status, alcohol consumption) and nutritional quality of the diet assessed by the adherence to the French food-based dietary guidelines, OF consumption was associated with a lower risk of T2D. Participants with the highest quintile of OF consumption, compared with those with the lowest quintile, had 35% lower risk of T2D (95% CI = 0.43–0.97). Each increment of 5% in the proportion of OF in the diet was associated with 3% lower risk of T2D (HR 0.97, 95% CI = 0.95–0.99). In this large prospective cohort study, OF consumption was inversely associated with the risk of T2D. Further experimental and prospective studies should be conducted to confirm these observations.
[Kesse-Guyot, E., Rebouillat, P., Payrastre, L., Allès, B., Fezeu, L.K., Druesne-Pecollo, N., Srour, B., Bao, W., Touvier, M., Galan, P. and Hercberg, S., 2020. International Journal of Behavioral Nutrition and Physical Activity, 17(1), pp.1-12.]
- Exposure to Persistent Organic Pollutants (POPs) and Their Relationship to Hepatic Fat and Insulin Insensitivity among Asian Indian Immigrants in the United States
Persistent organic pollutants (POPs), such as dichlorodiphenyltrichloroethane (DDT) and other organochlorine compounds, are abundant in the environment and in foodstuffs from the Indian subcontinent. These environmental contaminants have been associated with a higher risk of diabetes in numerous studies. Asian Indians are well known to have a high risk of diabetes compared with other populations, and this risk is also found in migrant populations of Asian Indians in the United States, Europe, and elsewhere. We hypothesized that high plasma concentrations of POPs in Asian Indian migrants are linked to a variety of diabetes-related pathologies and explored the mechanism for the induction of these effects. We measured 30 environmental pollutants in plasma samples obtained from 147 participants in the Metabolic syndrome and Atherosclerosis in South Asians Living in America pilot study using a gas chromatography–tandem mass spectrometry analytical method that uses less than 0.5 mL of plasma. We found that plasma levels of o,p′-DDT and p,p′-DDT were independently associated with both body mass index (BMI) and waist circumference. Doubling the levels of the sums of these DDTs was associated with insulin insensitivity (−0.38 Matsuda index, p = 0.001), increased adiposity (1.26 kg/m2 BMI and 3.58 cm waist circumference increase, p < 0.0001), circulating insulin (12.9 mIU/L, p = 0.002), hepatic fat (−0.051 HU, p = 0.001), as well as increased odds of obesity (OR = 2.17, p < 0.001, BMI-based; OR = 2.37, p = 0.001, waist-based), prediabetes (OR = 1.55, p = 0.02), diabetes (OR = 1.72, p = 0.01), and fatty liver (OR = 1.66, p = 0.01) in multivariable models accounting for confounding by age, sex, years in the US, education, and fish protein. Furthermore, levels of DDTs were associated with increased hepatic fat and circulating insulin, independent of obesity and confounders. These findings suggest that exposure to DDTs may contribute to the risk of metabolic disease among Asian Indians by affecting hepatic fat levels independent of obesity.
[La Merrill, M.A., Johnson, C.L., Smith, M.T., Kandula, N.R., Macherone, A., Pennell, K.D. and Kanaya, A.M., 2019. Environmental science & technology, 53(23), pp.13906-13918.]
- Elevated Levels of Organochlorine Pesticides in South Asian Immigrants Are Associated With an Increased Risk of Diabetes.
Rates of diabetes mellitus are higher in South Asians than in other populations and persist after migration. One unexplored cause may be higher exposure to persistent organic pollutants associated with diabetes in other populations. We compared organochlorine (OC) pesticide concentrations in South Asian immigrants and European whites to determine whether the disease was positively associated with OC pesticides in South Asians.South Asians of Tamil or Telugu descent (n = 120) and European whites (n = 72) were recruited into the London Life Sciences Population Study cohort. Blood samples as well as biometric, clinical, and survey data were collected. Plasma levels of p,p'-dichlorodiphenyldichloroethylene (DDE), p,p'- dichlorodiphenyltrichloroethane, β-hexachlorohexane (HCH), and polychlorinated biphenyl-118 were analyzed by gas chromatography-mass spectrometry. South Asian cases and controls were categorized by binary exposure (above vs below the 50th percentile) to perform logistic regression.Tamils had approximately threefold to ninefold higher levels of OC pesticides, and Telugus had ninefold to 30-fold higher levels compared with European whites. The odds of exposure to p,p'-DDE above the 50th percentile was significantly greater in South Asian diabetes cases than in controls (OR: 7.00; 95% CI: 2.22, 22.06). The odds of exposure to β-HCH above the 50th percentile was significantly greater in the Tamil cases than in controls (OR: 9.35; 95% CI: 2.43, 35.97).South Asian immigrants have a higher body burden of OC pesticides than European whites. Diabetes mellitus is associated with higher p,p'-DDE and β-HCH concentrations in this population. Additional longitudinal studies of South Asian populations should be performed.
[Daniels SI, Chambers JC, Sanchez SS, La Merrill MA, et al. 2018. J Endocr Soc. 2(8):832-841]
- Association between organic food consumption and metabolic syndrome: cross-sectional results from the NutriNet-Santé study.
Metabolic syndrome (MetS), a multicomponent condition, is a cardiovascular disease predictor. Although exposure to agricultural pesticides has been suggested as a potential contributor to the rising rates of obesity, type 2 diabetes, and other features of metabolic disorders, no studies have focused on the association between consumption of organic food (produced without synthetic pesticides) and MetS. We aimed to investigate the cross-sectional association between organic food consumption and MetS in French adults to determine whether it would be worth conducting further studies, particularly large prospective and randomised trials.A total of 8174 participants from the NutriNet-Santé study who attended a clinical visit and completed an organic food frequency questionnaire were included in this cross-sectional analysis.Higher organic food consumption was negatively associated with the prevalence of MetS: adjusted prevalence ratio was 0.69 (95% CI 0.61, 0.78) when comparing the third tertile of proportion of organic food in the diet with the first one (p value <0.0001). Higher consumption of organic plant-based foods was also related to a lower probability of having MetS. In addition, when stratifying by lifestyle factors (nutritional quality of the diet, smoking status, and physical activity), a significant negative association was detected in each subgroup (p values <0.05), except among smokers. Our results showed that a higher organic food consumption was associated with a lower probability of having MetS. Additional prospective studies and randomised trials are required to ascertain the relationship between organic food consumption and metabolic disorders.
[Baudry J, Lelong H, Adriouch S, Julia C, et al. 2017. Eur J Nutr. doi: 10.1007/s00394-017-1520-1. ]
- Exposure to DDT and diabetic nephropathy among Mexican Americans in the 1999-2004 National Health and Nutrition Examination Survey.
Concentrations of the pesticide DDT (dichlorodiphenyltrichloroethane) and its metabolite DDE (dichlorodiphenyldichloroethylene), in the blood of Mexican Americans, were evaluated to determine their relationships with diabetes and diabetic nephropathy. The data were derived from the National Health and Nutrition Examination Survey (NHANES) 1999-2004 (unweighted N = 1,411, population estimate = 13,760,609). The sample included teens, 12-19 years old, which accounted for 19.8% of the data. The time of the study overlapped the banning of DDT in Mexico in the year 2000, and those participants born in Mexico were exposed to DDT before they immigrated to the US. We sought to better understand the relationship of DDT with diabetes in a race/ethnicity group prone to develop diabetes and exposed to DDT. In this study, nephropathy was defined as urinary albumin to creatinine ratio >30 mg/g, representing microalbuminuria and macroalbuminuria, and total diabetes was defined as diagnosed and undiagnosed diabetes (glycohemoglobin, A1c ≥ 6.5%). The proportion with the isomer p,p'-DDT >0.086 ng/g (above the maximum limit of detection) was 13.3% for Mexican Americans born in the US, and 36.9% for those born in Mexico. Levels of p,p'-DDT >0.086 ng/g were associated with total diabetes with nephropathy (odds ratio = 4.42, 95% CI 2.23-8.76), and with total diabetes without nephropathy (odds ratio = 2.02, 95% CI 1.19-3.44). The third quartile of p,p'-DDE (2.99-7.67 ng/g) and the fourth quartile of p,p'-DDE (≥7.68 ng/g) were associated with diabetic nephropathy and had odds ratios of 5.32 (95% CI 1.05-26.87) and 14.95 (95% CI 2.96-75.48) compared to less than the median, respectively, whereas p,p'-DDE was not associated with total diabetes without nephropathy. The findings of this study differ from those of a prior investigation of the general adult US population in that there were more associations found with the Mexican Americans sample.
[Everett CJ, Thompson OM, Dismuke CE. Environ Pollut. 222:132-137.]
- Exposure to pesticides and the associated human health effects.
Pesticides are used widely to control weeds and insect infestation in agricultural fields and various pests and disease carriers (e.g., mosquitoes, ticks, rats, and mice) in houses, offices, malls, and streets. As the modes of action for pesticides are not species-specific, concerns have been raised about environmental risks associated with their exposure through various routes (e.g., residues in food and drinking water). Although such hazards range from short-term (e.g., skin and eye irritation, headaches, dizziness, and nausea) to chronic impacts (e.g., cancer, asthma, and diabetes), their risks are difficult to elucidate due to the involvement of various factors (e.g., period and level of exposure, type of pesticide (regarding toxicity and persistence), and the environmental characteristics of the affected areas). There are no groups in the human population that are completely unexposed to pesticides while most diseases are multi-causal to add considerable complexity to public health assessments. Hence, development of eco-friendly pesticide alternatives (e.g., EcoSMART) and Integrated Pest Management (IPM) techniques is desirable to reduce the impacts of pesticides. This paper was hence organized to present a comprehensive review on pesticides with respect to their types, environmental distribution, routes of exposure, and health impacts.
[Kim KH, Kabir E, Jahan SA. 2017. Sci Total Environ. 575:525-535.]
- Facts and Fallacies in the Debate on Glyphosate Toxicity.
The safety profile of the herbicide glyphosate and its commercial formulations is controversial. Reviews have been published by individuals who are consultants and employees of companies commercializing glyphosate-based herbicides in support of glyphosate's reapproval by regulatory agencies. These authors conclude that glyphosate is safe at levels below regulatory permissible limits. In contrast, reviews conducted by academic scientists independent of industry report toxic effects below regulatory limits, as well as shortcomings of the current regulatory evaluation of risks associated with glyphosate exposures. Two authors in particular (Samsel and Seneff) have published a series of commentaries proposing that long-term exposure to glyphosate is responsible for many chronic diseases (including cancers, diabetes, neuropathies, obesity, asthma, infections, osteoporosis, infertility, and birth defects). The aim of this review is to examine the evidential basis for these claimed negative health effects and the mechanisms that are alleged to be at their basis. We found that these authors inappropriately employ a deductive reasoning approach based on syllogism. We found that their conclusions are not supported by the available scientific evidence. Thus, the mechanisms and vast range of conditions proposed to result from glyphosate toxicity presented by Samsel and Seneff in their commentaries are at best unsubstantiated theories, speculations, or simply incorrect. This misrepresentation of glyphosate's toxicity misleads the public, the scientific community, and regulators. Although evidence exists that glyphosate-based herbicides are toxic below regulatory set safety limits, the arguments of Samsel and Seneff largely serve to distract rather than to give a rational direction to much needed future research investigating the toxicity of these pesticides, especially at levels of ingestion that are typical for human populations.
[Mesnage R, Antoniou MN. 2017. Front Public Health. 5:316]
- Human adipose tissue levels of persistent organic pollutants and metabolic syndrome components: Combining a cross-sectional with a 10-year longitudinal study using a multi-pollutant approach.
We aimed to assess the influence of long-term exposure to POPs on the risk of metabolic syndrome, combining a cross-sectional with a 10-year longitudinal follow-up design. Residues of eight POPs were quantified in adipose tissue samples from 387 participants recruited between 2003 and 2004 in Granada province (Spain). The outcome ("metabolically compromised") was defined as having ≥1 diagnosis of type 2 diabetes, hypertension, hypertriglyceridemia, and/or low HDL cholesterol. The cross-sectional analysis was conducted in the initial cohort, while the 10-year longitudinal analysis was conducted in those 154 participants free of any of the so-mentioned metabolic diseases and classified as "metabolically healthy" at recruitment. Statistical analyses were performed using single and multi-pollutant approaches through logistic and Cox regression analyses with elastic net penalty. After adjusting for confounders, β-hexachlorocyclohexane (β-HCH) and hexachlorobenzene (HCB) were independently associated with an increased risk of being metabolically compromised (unpenalized ORs=1.17, 95% CI=1.01-1.36 and 1.17, 95% CI=0.99-1.38, respectively). Very similar results were found in the 10-year longitudinal analysis [HRs=1.28, 95% CI=1.01-1.61 (β-HCH); 1.26, 95% CI=1.00-1.59 (HCB)] and were in line with those obtained using elastic net regression. Finally, when the arithmetic sum of both compounds was used as independent variable, risk estimates increased to OR=1.25, 95% CI=1.03-1.52 and HR=1.32, 95% CI=1.02-1.70. Our results suggest that historical exposure to HCB and β-HCH is consistently associated with the risk of metabolic disorders, and that these POPs might be partly responsible for the morbidity risk traditionally attributed to age and obesity.
[Mustieles V, Fernández MF, Martin-Olmedo P, et al. 2017. Environ Int. 104:48-57.]
- Imidacloprid Promotes High Fat Diet-Induced Adiposity in Female C57BL/6J Mice and Enhances Adipogenesis in 3T3-L1 Adipocytes via the AMPKα-Mediated Pathway.
Imidacloprid, a neonicotinoid insecticide, was previously reported to enhance adipogenesis and resulted in insulin resistance in cell culture models. It was also reported to promote high fat diet-induced obesity and insulin resistance in male C57BL/6J mice. Thus, the goal of the present study was to determine the effects of imidacloprid and dietary fat interaction on the development of adiposity and insulin resistance in female C57BL/6J mice. Mice were fed with a low (4% w/w) or high fat (20% w/w) diet containing imidacloprid (0.06, 0.6, or 6 mg/kg bw/day) for 12 weeks. Mice fed with imidacloprid (0.6 mg/kg bw/day) significantly enhanced high fat diet-induced weight gain and adiposity. Treatment with imidacloprid significantly increased serum insulin levels with high fat diet without effects on other markers of glucose homeostasis. AMPKα activation was significantly inhibited by 0.6 and 6 mg imidacloprid/kg bw/day in white adipose tissue. Moreover, AMPKα activation with 5-aminoimidazole-4-carboxamide ribonucleotide abolished the effects of imidacloprid (10 μM) on enhanced adipogenesis in 3T3-L1 adipocytes. N-Acetyl cysteine also partially reversed the effects of imidacloprid on reduced phosphorylation of protein kinase B (AKT) in C2C12 myotubes. These results indicate that imidacloprid may potentiate high fat diet-induced adiposity in female C57BL/6J mice and enhance adipogenesis in 3T3-L1 adipocytes via the AMPKα-mediated pathway. Imidacloprid might also influence glucose homeostasis partially by inducing cellular oxidative stress in C2C12 myotubes.
[Sun Q, Qi W, Xiao X, Yang SH, et al. 2017. J Agric Food Chem. 65(31):6572-6581]
- Persistent organic pollutants and risk of diabetes and obesity on healthy adults: Results from a cross-sectional study in Spain.
Environmental exposure to persistent organic pollutants (POPs) has been reported to be relevant in the population of the Canary Islands (Spain), especially that of organochlorine pesticides. On the other hand, the population of this archipelago presents a high prevalence of type 2 diabetes (T2D), and it has been recently reported that environmental chemical contamination could play a role in the development of this disease. Researchers performed a cross-sectional study in a representative sample from this archipelago to evaluate whether serum levels of selected POPs could be considered as risk factors for diabetes in this population. Serum levels of 30 POPs were determined in 429 adults (9.3% with T2D). Serum levels of p,p'-DDE (DDE), PCB-153 and PCB-118 were significantly higher among subjects having diabetes than in non-diabetic subjects (p=0.001, p=0.046, and p<0.0001, respectively). A positive correlation between serum p,p'-DDE and glucose levels was observed. Serum p,p'-DDE was identified as a risk factor for diabetes in univariate analysis in the whole series, and it remained as an independent risk factor for diabetes in subjects with serum glucose <126mg/dL (multivariate analysis, Exp(B)=1.283, CI 95% (1.023-1.611), p=0.031). Those normoglycemic subjects that are most exposed to p,p'-DDE (95th percentile: serum p,p'-DDE>5μg/L) seem to be those people at higher risk. Results showed that p,p'-DDE levels were significantly higher among subjects having diabetes. These findings should be considered by public health Authorities to implement measures devoted to minimize human exposure to pollutants that could be harmful to the population.
[Henríquez-Hernández LA, Luzardo OP, Valerón PF, et al. 2017. Sci Total Environ. 607-608:1096-1102.]
- Persistent organic pollutants in early pregnancy and risk of gestational diabetes mellitus.
Persistent organic pollutants (POPs) are a group of diverse substances, including polychlorinated biphenyls (PCBs) and organochlorine pesticides that are resistant to biodegradation and ubiquitously present in our environment. Exposure to endocrine disrupting chemicals such as POPs has been linked to type 2 diabetes and metabolic disturbances in epidemiological and animal studies, but little is known about POPs exposure during pregnancy and the development of gestational diabetes mellitus (GDM). The purpose of this study was to determine the extent to which exposure to current low levels of different POPs in the first trimester of pregnancy is associated with GDM risk in 939 women from the "Rhea" pregnancy cohort in Crete, Greece. Concentrations of several PCBs, dichlorodiphenyldichloroethene (DDE), and hexachlorobenzene (HCB) were determined in first trimester maternal serum by triple quadrupole mass spectrometry. Pregnant women were screened for gestational diabetes mellitus (GDM) between 24 and 28weeks of gestation, and GDM was defined by the criteria proposed by Carpenter and Coustan. Of the 939 women, 68 (7%) developed GDM. Serum concentrations of POPs were higher in women with GDM. Women in the medium and high tertiles of PCBs had 3.90 (95% CI: 1.37, 11.06) and 3.60 (95% CI: 1.14, 11.39) fold respectively higher odds of developing GDM compared to women in the lowest tertile of PCB exposure after adjusting for pre-pregnancy BMI and several other confounders. Odds of GDM for women in the medium and high tertiles of dioxin-like PCBs was 5.63 (95% CI: 1.81, 17.51) and 4.71 (95% CI: 1.38, 16.01) and for nondioxin-like PCBs 2.36 (95% CI: 0.89, 6.23) and 2.26 (95% CI: 0.77, 6.68) respectively. Prenatal DDE and HCB exposure were not significantly associated GDM risk.These findings suggest that women with high PCBs levels in early pregnancy had higher risk for GDM. Further studies are needed to replicate these results and to evaluate potential biological mechanisms underlying the observed associations.
[Vafeiadi M, Roumeliotaki T, Chalkiadaki G, Rantakokko P, et al. Environ Int;98:89-95]
- Potential contribution of insecticide exposure and development of obesity and type 2 diabetes.
The introduction of insecticides has greatly improved agricultural productivity and human nutrition; however, the wide use of insecticides has also sparked growing concern over their health impacts. Increased rate of cancers, neurodegenerative disorders, reproductive dysfunction, birth defects, respiratory diseases, cardiovascular diseases and aging have been linked with insecticide exposure. Meanwhile, a growing body of evidence is suggesting that exposure to insecticides can also potentiate the risk of obesity and type 2 diabetes. This review summarizes the relationship between insecticide exposure and development of obesity and type 2 diabetes using epidemiological and rodent animal studies, including potential mechanisms. The evidence as a whole suggests that exposure to insecticides is linked to increased risk of obesity and type 2 diabetes.
[Xiao X, Clark JM2, Park Y. 2017. Food Chem Toxicol. 105:456-474]
- Understanding Epigenetic Effects of Endocrine Disrupting Chemicals: from Mechanisms to Novel Test Methods.
Endocrine disrupting chemicals (EDCs) are man-made chemicals that interfere with hormonal signalling pathways. They are used in, e.g., production of common household materials, in resin-based medical supplies, pesticides. Thus, they are environmentally ubiquitous and humans and wildlife are exposed to them on a daily basis. Early life exposure to EDCs has been associated with later life adversities such as obesity, diabetes and cancer. Mechanisms underlying such associations are unknown but are likely to be mediated by epigenetic changes induced by EDCs. Epigenetics is the study of changes in gene function that are heritable but do not entail a change in DNA sequence. EDCs have been shown to affect epigenetic marks such as DNA methylation and histone modifications. The scope of this article is to review today's knowledge about mechanisms involved in EDC-induced epigenetic changes and to discuss how this knowledge could be used for designing novel methods addressing epigenetic effects of EDCs.
[Alavian-Ghavanini A, Rüegg J. 2017. Basic Clin Pharmacol Toxicol. doi: 10.1111/bcpt.12878.]
- Glyphosate pathways to modern diseases V: Amino acid analogue of glycine in diverse proteins
Glyphosate, a synthetic amino acid and analogue of glycine, is the most widely used biocide on the planet. Its presence in food for human consumption and animal feed is ubiquitous. Epidemiological studies have revealed a strong correlation between the increasing incidence in the United States of a large number of chronic diseases and the increased use of glyphosate herbicide on corn, soy and wheat crops. Glyphosate, acting as a glycine analogue, may be mistakenly incorporated into peptides during protein synthesis. A deep search of the research literature has revealed a number of protein classes that depend on conserved glycine residues for proper function. Glycine, the smallest amino acid, has unique properties that support flexibility and the ability to anchor to the plasma membrane or the cytoskeleton. Glyphosate substitution for conserved glycines can easily explain a link with diabetes, obesity, asthma, chronic obstructive pulmonary disease (COPD), pulmonary edema, adrenal insufficiency, hypothyroidism, Alzheimer’s disease, amyotrophic lateral sclerosis (ALS), Parkinson’s disease, prion diseases, lupus, mitochondrial disease, nonHodgkin’s lymphoma, neural tube defects, infertility, hypertension, glaucoma, osteoporosis, fatty liver disease and kidney failure. The correlation data together with the direct biological evidence make a compelling case for glyphosate action as a glycine analogue to account for much of glyphosate’s toxicity. Glufosinate, an analogue of glutamate, likely exhibits an analogous toxicity mechanism. There is an urgent need to find an effective and economical way to grow crops without the use of glyphosate and glufosinate as herbicides.
[Samsel, A. and Seneff, S., 2016. J Biol Phys Chem, 16(6), pp.9-46.]
- Occupational exposure to pesticides as a possible risk factor for the development of chronic diseases in humans (Review).
It is well known that pesticides are widely used compounds. In fact, their use in agriculture, forestry, fishery and the food industry has granted a huge improvement in terms of productive efficiency. However, a great number of epidemiological surveys have demonstrated that these toxic compounds can interact and exert negative effects not only with their targets (pests, herbs and fungi), but also with the rest of the environment, including humans. This is particularly relevant in the case of workers involved in the production, transportation, preparation and application of these toxicants. Accordingly, a growing body of evidence has demonstrated the correlation between occupational exposure to pesticides and the development of a wide spectrum of pathologies, ranging from eczema to neurological diseases and cancer. Pesticide exposure is often quite difficult to establish, as many currently used modules do not take into account all of the many variables that can occur in a diverse environment, such as the agricultural sector, and the assessment of the real risk for every single worker is problematic. Indeed, the use of personal protection equipment is necessary while handling these toxic compounds, but education of workers can be even more important: personal contamination with pesticides may occur even in apparently harmless situations. This review summarises the most recent findings describing the association between pesticide occupational exposure and the development of chronic diseases.
[Gangemi S, Miozzi E, Teodoro M, Briguglio G, et al. 2016. Mol Med Rep. 14(5):4475-4488. ]
- Adulthood dietary exposure to a common pesticide leads to an obese-like phenotype and a diabetic profile in apoE3 mice.
Increasing evidence links the widespread exposure to organophosphate (OP) pesticides to the global epidemics of type 2 diabetes and obesity. Recent data highlighted gene×environment interactions: mice expressing the human apolipoprotein E3 (apoE3) isoform were more prone to develop obesity than those expressing apoE2 or apoE4 upon dietary challenge with chlorpyrifos (CPF), the most used OP worldwide. Study aimed to further explore the contribution of the APOE3 genotype on the emergence of obesity and related metabolic dysfunctions upon subchronic exposure to CPF. Seven-month-old targeted replacement apoE3 and C57BL/6N male mice were orally exposed to CPF at 0 or 2mg/kg body weight/day for 8 consecutive weeks. CPF exposure generally increased food ingestion, glucose and total cholesterol concentrations, and tended to elevate acyl ghrelin levels. Nonetheless, excess weight gain and increased leptin levels were inherent to apoE3 mice. Moreover, the propensity towards a diabetic profile was markedly higher in these animals than in C57BL/6N, as they showed a higher homeostatic model assessment for insulin resistance index and higher insulin levels. Although both genotypes were metabolically affected by CPF, the results of the present investigation revealed that apoE3 mice were the most vulnerable to developing obesity and related disturbances following CPF administration through the diet. Since the APOE3 genotype is the most prevalent worldwide, current findings have particular implications for human health.
[Peris-Sampedro F, Cabré M, Basaure P, Reverte I, et al. 2015. Environ Res. 142:169-76]
- Association of persistent organic pollutants and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia: A systematic review.
Over half of the people with diabetes in the world live in Asia. Emerging scientific evidence suggests that diabetes is associated with environmental pollutants, exposures that are also abundant in Asia.
The aim of this study was to systematically review the literature concerning the association of persistent organic pollutants (POPs) and non-persistent pesticides with diabetes and diabetes-related health outcomes in Asia. A total of 19 articles met the inclusion criteria and were evaluated in this review. To date, the evidence relating POPs and non-persistent pesticides with diabetes in Asian populations is equivocal. Positive associations were reported between serum concentrations of polychlorinated dibenzodioxins and dibenzofurans (PCDD/Fs), polychlorinated biphenyls (PCBs), and several organochlorine pesticides (DDT, DDE, oxychlordane, trans-nonachlor, hexachlorobenzene, hexachlorocyclohexane) with diabetes. PCDD/Fs were also associated with blood glucose and insulin resistance, but not beta-cell function. There were substantial limitations of the literature including: most studies were cross-sectional, few studies addressed selection bias and confounding, and most effect estimates had exceptionally wide confidence intervals. Few studies evaluated the effects of organophosphates. Well-conducted research is urgently needed on these pervasive exposures to inform policies to mitigate the diabetes epidemic in Asia.
[Jaacks LM and Staimez LR. 2015. Environ Int. 76:57-70]
- Persistent organic pollutants in young adults and changes in glucose related metabolism over a 23-year follow-up.
Substantial evidence associates persistent organic pollutants (POP) with metabolic disturbances related to diabetes, but longitudinal studies with repeated measures are scarce. Study aimed to characterize the association between background exposures to POPs with repeated measures of glucose homeostasis over 23-years.Study measured POPs in serum obtained in 1987-88 (follow-up year 2) in 90 non-diabetic controls and 90 cases diabetes-free at year 2 who became diabetic by year 20. 32 POPs were detectable in ≥75% of participants and created summary scores for 32 POPs, 23 polychlorinated biphenyls (PCB), and 8 organochlorine pesticides (OCP). Dependent variables were measures of glucose homeostasis at years 0-25 (up to 8 examinations).The associations between the three summary scores and measures of glucose homeostasis were present for observations at ages 40-55 years, and particularly between 48-55 years. No associations were observed at younger ages.Glucose homeostasis may worsen after decades of exposure to PCBs and OCPs at background environmental levels, independent of BMI and after participants reached the 5th decade of life.
[Suarez-Lopez JR, Lee DH, Porta M, et al. 2015. Environ Res. 137:485-94.]
- Exposure to Organochlorine Pollutants and Type 2 Diabetes: A Systematic Review and Meta-Analysis
Though exposure to organochlorine pollutants (OCPs) is considered a risk factor for type 2 diabetes (T2DM), epidemiological evidence for the association remains controversial. A systematic review and meta-analysis was applied to quantitatively evaluate the association between exposure to OCPs and incidence of T2DM and pool the inconsistent evidence. Quantitative estimates and information regarding study characteristics were extracted from 23 original studies. We retrieved 23 eligible articles to conduct this meta-analysis. OR (odds ratio) or RR (risk ratio) estimates in each subgroup were discussed, and the strong associations were observed in PCB-153 , PCBs , and p,p′-DDE based on a random-effects model. This meta-analysis provides quantitative evidence supporting the conclusion that exposure to organochlorine pollutants is associated with an increased risk of incidence of T2DM.
[Tang M, Chen,K et al. 2014. PLoS One. 9(10): e85556.]
- Is cumulated pyrethroid exposure associated with prediabetes? A cross-sectional study.
Pyrethroids are a class of insecticides used widely for vector control programs. Acute pyrethroid poisoning is rare, but well documented, whereas effects of cumulative exposure are insufficiently described, including possible negative effect on glucose regulation. The objective of this study was to investigate an association between exposure to pyrethroids and abnormal glucose regulation (prediabetes or diabetes). A cross-sectional study was performed among 116 pesticide sprayers from public vector control programs in Bolivia and 92 nonexposed controls. Blood samples were analyzed for glycosylated hemoglobin (HbA1c), a measure of glucose regulation. No association was found between pyrethroid exposure and diabetes symptoms. The prevalence of abnormal glucose regulation (defined as HbA1c ≥ 5.6%) was 61.1% among sprayers and 7.9% among nonexposed controls, corresponding to an adjusted odds ratio for all sprayers of 11.8 [4.2-33.2] and 18.5 [5.5-62.5] for pyrethroid-exposed only. Among sprayers who had only used pyrethroids, a significant positive trend was observed between cumulative pesticide exposure (total number of hours sprayed) and adjusted OR of abnormal glucose regulation, with OR 14.7 [0.9-235] in the third exposure quintile. The study found a severely increased prevalence of prediabetes among Bolivian pesticide sprayers compared with a control group, but the relevance of the control group is critical. Within the spraying group, an association between cumulative exposure to pyrethroids and abnormal glucose regulation was seen. Further studies are needed to confirm this association.
[Hansen MR, Jørs E, Lander F, et al. 2014. J Agromedicine. 19(4):417-26]
- Pesticide use and incident diabetes among wives of farmers in the Agricultural Health Study
Study ained to estimate associations between use of specific agricultural pesticides and incident diabetes in women. Researchers used data from the Agricultural Health Study, a large prospective cohort of pesticide applicators and their spouses in Iowa and North Carolina. Data was limited analysis to 13 637 farmers' wives who reported ever personally mixing or applying pesticides at enrolment (1993-1997), who provided complete data on required covariates and diabetes diagnosis and who reported no previous diagnosis of diabetes at enrolment. Participants reported ever-use of 50 specific pesticides at enrolment and incident diabetes at one of two follow-up interviews within an average of 12 years of enrolment. Five pesticides were positively associated with incident diabetes: three organophosphates, fonofos, phorate and parathion; the organochlorine dieldrin; and the herbicide 2,4,5-T/2,4,5-TP. With phorate and fonofos together in one model to account for their correlation, risks for both remained elevated, though attenuated compared with separate models. Results are consistent with previous studies reporting an association between specific organochlorines and diabetes and add to growing evidence that certain organophosphates also may increase risk.
[Starling AP, Umbach DM, Kamel F, et al. 2014. Occup Environ Med. 71(9):629-35]
- Growing burden of diabetes in Sub-Saharan Africa: contribution of pesticides ?
The diabetes burden is growing in Sub-Saharan Africa (SSA). The low overall access to health care has been documented to contribute to the high diabetes-related mortality. Due to economic, demographic, epidemiological and nutrition transitions in SSA, the growing prevalence of diabetes appears to be related to obesogenic lifestyles and the intergenerational impact of malnutrition in women of childbearing age. Both overnutrition and undernutrition have been associated with the development of diabetes and other chronic diseases. Africans are also suspected of being genetically predisposed to diabetes. According to existing data in developed countries, exposure to pesticides, particularly organochlorines and metabolites, is associated with a higher risk of developing type 2 diabetes and its comorbidities. In African countries, pesticide exposure levels often appear much higher than in developed countries. Furthermore, undernutrition, which is still highly prevalent in SSA, could increase susceptibility to the adverse effects of organic pollutants. Therefore, the growing and inadequate use of pesticides may well represent an additional risk factor for diabetes in SSA. Additionally, high exposure to pesticides in African infants in utero and during the perinatal period may increase the intergenerational risk of developing diabetes in SSA.
[Azandjeme CS, Bouchard M, Fayomi B, et al. 2013. Curr Diabetes Rev. 9(6):437-49]
- Pesticides and human diabetes: a link worth exploring?
Traditionally, the risk factors for diabetes have largely focused on genetics and lifestyle. Great emphasis is placed on lifestyle measures and finding novel pharmacological treatment options to combat diabetes, but there is increasing evidence linking environmental pollutants, especially pesticides, to the development of insulin resistance and Type 2 diabetes. Pesticide use has increased dramatically worldwide and the effects of pesticides on glucose metabolism are too significant for a possible diabetogenic link to be dismissed. The aim of this review article was to assess the links between pesticides and human diabetes with the goal of stimulating further research in this area.
[Swaminathan K. 2013. Diabet Med. 30(11):1268-71]
- Sublethal exposures of diazinon alters glucose homostasis in Wistar rats: Biochemical and molecular evidences of oxidative stress in adipose tissues.
Disorder of glucose homeostasis is one of the most important complications following exposure to organophosphorous (OPs) pesticides. The present study focused on tumor necrosis factor alpha (TNFα), glucose transporter type 4 (GLUT4), and nuclear factor kappa-light-chain-enhancer of activated B cells (Nf-κB) in a sublethal model of toxicity by diazinon as a common OPs. Animals were treated for 4 weeks and serum insulin was measured in fasting condition. In adipose tissue, oxidative stress markers including reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and TNFα were evaluated. The mRNA expression of GLUT4, Nf-κB and glyceraldehyde 3-phosphate dehydrogenase (GAPDH) were also determined by real time reverse transcription polymerase chain reaction (RT-PCR). Diazinon at dose of 70mg/kg/day impaired GTT and diminished insulin level while augmented ROS, NADPH oxidase, and TNFα. On the basis of biochemical and molecular findings, it is concluded that diazinon impairs glucose homeostasis through oxidative stress and related proinflammatory markers in a way to result in a reduced function of insulin inside adipose tissue. Although, diazinon interfered with pancreatic influence on the adipose tissue most probably via stimulation of muscarinic receptors, current data are not sufficient to introduce adipose tissue as a target organ to OPs toxicity. Considering the potential of OPs to accumulate in adipose tissue, it seems a good candidate organ for future studies. Although, hyperglycemia was not induced by diazinon but increased AUC0-180min leads us to the point that diazinon induces kind of instability in glucose homostasis and diabetes.
[Pakzad M, Fouladdel S, et al. 2013. Pestic Biochem Physiol. 105(1):57-61]
- Does early-life exposure to organophosphate insecticides lead to prediabetes and obesity
Researchers gave neonatal rats chlorpyrifos, diazinon or parathion in doses devoid of any acute signs of toxicity, straddling the threshold for barely-detectable cholinesterase inhibition. Organophosphate exposure during a critical developmental window altered the trajectory of hepatic adenylyl cyclase/cyclic AMP signaling, culminating in hyperresponsiveness to gluconeogenic stimuli. Consequently, the animals developed metabolic dysfunction resembling prediabetes. When the organophosphate-exposed animals consumed a high fat diet in adulthood, metabolic defects were exacerbated and animals gained excess weight compared to unexposed rats on the same diet. At the same time, the high fat diet ameliorated many of the central synaptic defects caused by organophosphate exposure, pointing to nonpharmacologic therapeutic interventions to offset neurodevelopmental abnormalities, as well as toward fostering dietary choices favoring high fat intake. These studies show how common insecticides may contribute to the increased worldwide incidence of obesity and diabetes.
[Slotkin, T.A. 2011. Reproductive Toxicology. 31: 297–301.]
- An Environment-Wide Association Study (EWAS) on Type 2 Diabetes Mellitus
An analysis of 266 potential environmental contributors to type 2 diabetes links the disease to individuals who have higher levels of polychlorinated biphenyls (PCBs) and the pesticide heptachlor, as well a form of vitamin E found at high levels in soybean and corn oil. The researchers used NHANES data from 1999 to 2006. Type 2 diabetes prevalence among those with high levels of heptachlor epoxide, a breakdown product of heptachlor, was about two times higher than those with low levels of the compound.
[Patel CJ, et al. 2010. PLoS ONE 5(5): e10746.]
- Low Dose of Some Persistent Organic Pollutants Predicts Type 2 Diabetes: A Nested Case–Control Study
Study links low dose exposure to some persistent organic pollutants (POPs) to type 2 diabetes. The authors report that some POPs, including highly chlorinated PCBs, PBB153 and the organochlorine insecticides trans-nonachlor, oxychlordane and mirex, were associated with type 2 diabetes over an 18-year period, especially in obsese people. However, POPs did not show a traditional dose–response relationship with diabetes. Instead, POPs showed strong associations at relatively low exposures. The authors conclude that exposure to relatively low concentrations of certain POPs may play a role in the increased incidence of diabetes in the United States.
[Lee D-H, et al. 2010. Environ Health Perspect 118(9): doi:10.1289/ehp.0901480]
- Arsenic Exposure and Prevalence of Type 2 Diabetes in US Adults
Using National Health and Nutrition Examination Survey (NHANES) data, this study investigates the association of arsenic exposure, as measured in urine, with the prevalence of type 2 diabetes in a representative sample of US adults. Common sources of inorganic arsenic exposure include dietary exposure, drinking water pollution, and contamination associated with arsenic wood preservatives such as sawdust, smoke, direct contact, and hazardous waste sites. After adjustment for diabetes risk factors and markers of seafood intake, participants with type 2 diabetes had a 26% higher level of total arsenic (95% confidence interval [CI], 2.0%-56.0%) than participants without type 2 diabetes.
[Navas-Acien, Ana, et al. 2008. JAMA. 300(7):814-822]
- Environmental pollution and diabetes: a neglected association
Using cross-sectional data from the 1999–2002 National Health and Nutrition Examination Survey (NHANES), University of Cambridge scientists reported a strong correlation between insulin resistance (which can lead to adult onset diabetes) and serum concentrations of persistent organic pollutants (POPs), especially for organochlorine pesticide compounds. The scientists are advocating additional research into the little understood links between environmental pollution and adult onset diabetes.
[Oliver, AH et al. 2008. The Lancet, Vol. 371, Issue 9609, Pages 287-288]
- Incident Diabetes and Pesticide Exposure among Licensed Pesticide Applicators: Agricultural Health Study, 1993–2003
Exposure to certain environmental toxicants may be associated with increased risk of developing diabetes. The authors' aim was to investigate the relation between lifetime exposure to specific agricultural pesticides and diabetes incidence among pesticide applicators. The study included 33,457 licensed applicators, predominantly non-Hispanic White males, enrolled in the Agricultural Health Study. Incident diabetes was self-reported in a 5-year follow-up interview (1999–2003), giving 1,176 diabetics and 30,611 nondiabetics for analysis. Lifetime exposure to pesticides and covariate information were reported by participants at enrollment (1993–1997). Using logistic regression, the authors considered two primary measures of pesticide exposure: ever use and cumulative lifetime days of use. They found seven specific pesticides (aldrin, chlordane, heptachlor, dichlorvos, trichlorfon, alachlor, and cyanazine) for which the odds of diabetes incidence increased with both ever use and cumulative days of use. Applicators who had used the organochlorine insecticides aldrin, chlordane, and heptachlor more than 100 lifetime days had 51%, 63%, and 94% increased odds of diabetes, respectively. The observed association of organochlorine and organophosphate insecticides with diabetes is consistent with results from previous human and animal studies. Long-term exposure from handling certain pesticides, in particular, organochlorine and organophosphate insecticides, may be associated with increased risk of diabetes.
[Montgomery et al. American Journal of Epidemiology 2008 167(10):1235-1246]
- Pesticide Exposure and Self-Reported Gestational Diabetes Mellitus in the Agricultural Health Study
Study finds exposure of pregnant women to agricultural pesticides during the first trimester may double the risk of gestational diabetes. The study group was comprised of 11,273 women married to licensed pesticide applicators. Agricultural pesticide exposure during pregnancy, such as mixing or applying pesticides or repairing pesticide application equipment, resulted in an odds ratio of 2.2 (95% CI 1.5-3.3).
[Saldana, T., et al. Diabetes Care. March 2007 30:529-534]
- A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999-2002
Cross-sectional associations of the serum concentrations of persistent organic pollutants (POPs) with diabetes prevalence were investigated in 2,016 adult participants in the National Health and Nutrition Examination Survey 1999-2002. Six POPs (2,2',4,4',5,5'-hexachlorobiphenyl, 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin, 1,2,3,4,6,7,8,9-octachlorodibenzo-p-dioxin, oxychlordane, p,p'-dichlorodiphenyltrichloroethane, and trans-nonachlor) were selected, because they were detectable in >or=80% of participants. Compared with subjects with serum concentrations below the limit of detection, after adjustment for age, sex, race and ethnicity, poverty income ratio, BMI, and waist circumference, diabetes prevalence was strongly positively associated with lipid-adjusted serum concentrations of all six POPs. The association was consistent in stratified analyses and stronger in younger participants, Mexican Americans, and obese individuals. There were striking dose-response relations between serum concentrations of six selected POPs and the prevalence of diabetes. The strong graded association could offer a compelling challenge to future epidemiologic and toxicological research.
[Lee DH, Lee IK, Song K, Steffes M, Toscano W, et al. 2006. Diabetes Care. 29(7):1638-44.]
- Increased Rate of Hospitalization for Diabetes and Residential Proximity of Hazardous Waste Sites
Study finds increased rate of hospitalization for diabetes in those who live close to hazardous waste sites containing persistent organic pollutants (POPs), including pesticides. The rate ratios for diabetes discharges for people residing in POP sites, after adjustment for potential confounders were 1.23 [95% confidence interval (CI), 1.15–1.32]. In a subset of POP sites along the Hudson River, where there is higher income, less smoking, better diet, and more exercise, the rate ratio was 1.36 (95% CI, 1.26–1.47) compared to clean sites.
[Kouznetsova M, et al. 2006 Environ Health Perspect 115(1)]