Faculty Bibliography

Few studies have examined docosahexaenoic acid (DHA) in pregnant and lactating women in developing countries like China, where DHA-enriched supplements are increasingly popular. We aimed to assess the DHA status among Chinese pregnant and lactating women residing areas differing in the availability of aquatic products. In total, 1211 women in mid-pregnancy (17 +/- 2 weeks), late pregnancy (39 +/- 2 weeks), or lactation (42 +/- 7 days) were enrolled from Weihai (coastland), Yueyang (lakeland), and Baotou (inland) city, with approximately 135 women in each participant group by region. DHA concentrations were measured using capillary gas chromatography, and are reported as weight percent of total fatty acids. Mean plasma DHA concentrations were higher in coastland (mid-pregnancy 3.19%, late pregnancy 2.54%, lactation 2.24%) and lakeland women (2.45%, 1.95%, 2.26%) than inland women (2.25%, 1.67%, 1.68%) (p values < 0.001). Similar differences were observed for erythrocyte DHA. We conclude that DHA concentrations of Chinese pregnant and lactating women are higher in coastland and lakeland regions than in inland areas. DHA status in the study population appears to be stronger than populations from other countries studied to date.

Phthalates are environmental chemicals widely used in consumer and personal care products. In this study, we examined associations of urinary phthalates with blood pressure, triglycerides, and lipoproteins in children and adolescents, performing a cross-sectional analysis of a subsample of US children 6 to 19 years of age who participated in the National Health and Nutrition Examination Survey between the years 2009 and 2012. We quantified exposure to common environmental phthalates, with a focus on the dietary contaminant di-2-ethylhexylphthalate and 2 increasingly used replacements, di-isononyl phthalate and di-isodecyl phthalate, based on micromolar concentration of urinary metabolites. We assessed descriptive, univariate, and multivariable associations with blood pressure and lipids. Controlling for an array of sociodemographic and behavioral factors, as well as diet and body mass, metabolites of di-2-ethylhexylphthalate, di-isononyl phthalate, and di-isodecyl phthalate were associated with higher age-, sex- and height-standardized blood pressure. For each log unit increase in di-isodecyl phthalate metabolites, a 0.105 standard deviation unit increase in systolic blood pressure z score was identified (P=0.004); for di-isononyl phthalate metabolites, a 0.113 standard deviation unit increment was identified (P=0.008). For di-2-ethylhexylphthalate metabolites, a 0.103 standard deviation unit increment (P=0.013) was detected. Metabolites of low molecular weight phthalates commonly found in cosmetics and personal care products showed an association with blood pressure (>/=90th percentile) in univariate analysis, but this was no longer significant in our full multivariable model, suggesting specificity. Phthalate metabolites were not associated with triglycerides or high-density lipoproteins. Further, longitudinal studies are needed to confirm these associations and to assess opportunities for intervention.

CONTEXT: Di-isononyl phthalate (DINP) and di-isodecyl phthalate (DIDP) are environmental chemicals increasingly used to replace di-2-ethylhexylphthalate (DEHP) and commonly found in processed foods. Phthalate exposures, in particular DEHP, have been associated with insulin resistance in adolescents, but there are no data regarding the two substitutes, DINP and DIDP. OBJECTIVE: This study aimed to examine associations of DINP, DIDP, and DEHP with insulin resistance outcomes. DESIGN, SETTING, AND PARTICIPANTS: This was a cross-sectional analysis of 2009-2012 National Health and Nutrition Examination Surveys (NHANES) composed of 356 fasting 12-19-year-olds. MAIN OUTCOME MEASURES: Insulin resistance as a categorical outcome expressed as homeostatic model assessment of insulin resistance (HOMA-IR), using a cut point of 4.39 to define insulin resistance. We also examined continuous HOMA-IR as an outcome in secondary analyses. RESULTS: Controlling for demographic and behavioral factors, diet, age, body mass index, and urinary creatinine, for each log increase in DINP metabolite, a 0.08 (P = .001) increase in HOMA-IR was identified. Compared with the first tertile of DINP (23.4% adjusted prevalence), the third tertile was associated with a 34.4% prevalence (95% confidence interval [CI], 27.3-41.6%; P = .033) of insulin resistance. Similarly, compared with the first tertile of DEHP (20.5% adjusted prevalence), the third tertile had 37.7% prevalence (95% CI 29.8-45.6%; P = .003). CONCLUSIONS: Urinary DINP concentrations were associated with increased insulin resistance in this cross-sectional study of adolescents. The previously identified association of DEHP with insulin resistance was also confirmed. Further, longitudinal studies are needed to confirm these associations, with the possibility to assess opportunities for intervention.

The global incidence of chronic kidney disease (CKD) is increasing among individuals of all ages. Despite advances in proteomics, genomics and metabolomics, there remains a lack of safe and effective drugs to reverse or stabilize renal function in patients with glomerular or tubulointerstitial causes of CKD. Consequently, modifiable risk factors that are associated with a progressive decline in kidney function need to be identified. Numerous reports have documented the adverse effects that occur in response to graded exposure to a wide range of environmental chemicals. This Review summarizes the effects of such chemicals on four aspects of cardiorenal function: albuminuria, glomerular filtration rate, blood pressure and serum uric acid concentration. We focus on compounds that individuals are likely to be exposed to as a consequence of normal consumer activities or medical treatment, namely phthalates, bisphenol A, polyfluorinated alkyl acids, dioxins and furans, polycyclic aromatic hydrocarbons and polychlorinated biphenyls. Environmental exposure to these chemicals during everyday life could have adverse consequences on renal function and might contribute to progressive cumulative renal injury over a lifetime. Regulatory efforts should be made to limit individual exposure to environmental chemicals in an attempt to reduce the incidence of cardiorenal disease.

CONTEXT: Epidemiological studies and animal models demonstrate that endocrine-disrupting chemicals (EDCs) contribute to cognitive deficits and neurodevelopmental disabilities. OBJECTIVE: The objective was to estimate neurodevelopmental disability and associated costs that can be reasonably attributed to EDC exposure in the European Union. DESIGN: An expert panel applied a weight-of-evidence characterization adapted from the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and approximate burden of disease. Cost estimation as of 2010 utilized lifetime economic productivity estimates, lifetime cost estimates for autism spectrum disorder, and annual costs for attention-deficit hyperactivity disorder. Setting, Patients and Participants, and Intervention: Cost estimation was carried out from a societal perspective, ie, including direct costs (eg, treatment costs) and indirect costs such as productivity loss. RESULTS: The panel identified a 70-100% probability that polybrominated diphenyl ether and organophosphate exposures contribute to IQ loss in the European population. Polybrominated diphenyl ether exposures were associated with 873 000 (sensitivity analysis, 148 000 to 2.02 million) lost IQ points and 3290 (sensitivity analysis, 3290 to 8080) cases of intellectual disability, at costs of euro9.59 billion (sensitivity analysis, euro1.58 billion to euro22.4 billion). Organophosphate exposures were associated with 13.0 million (sensitivity analysis, 4.24 million to 17.1 million) lost IQ points and 59 300 (sensitivity analysis, 16 500 to 84 400) cases of intellectual disability, at costs of euro146 billion (sensitivity analysis, euro46.8 billion to euro194 billion). Autism spectrum disorder causation by multiple EDCs was assigned a 20-39% probability, with 316 (sensitivity analysis, 126-631) attributable cases at a cost of euro199 million (sensitivity analysis, euro79.7 million to euro399 million). Attention-deficit hyperactivity disorder causation by multiple EDCs was assigned a 20-69% probability, with 19 300 to 31 200 attributable cases at a cost of euro1.21 billion to euro2.86 billion. CONCLUSIONS: EDC exposures in Europe contribute substantially to neurobehavioral deficits and disease, with a high probability of >euro150 billion costs/year. These results emphasize the advantages of controlling EDC exposure.

CONTEXT: Rapidly increasing evidence has documented that endocrine-disrupting chemicals (EDCs) contribute substantially to disease and disability. OBJECTIVE: The objective was to quantify a range of health and economic costs that can be reasonably attributed to EDC exposures in the European Union (EU). DESIGN: A Steering Committee of scientists adapted the Intergovernmental Panel on Climate Change weight-of-evidence characterization for probability of causation based upon levels of available epidemiological and toxicological evidence for one or more chemicals contributing to disease by an endocrine disruptor mechanism. To evaluate the epidemiological evidence, the Steering Committee adapted the World Health Organization Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group criteria, whereas the Steering Committee adapted definitions recently promulgated by the Danish Environmental Protection Agency for evaluating laboratory and animal evidence of endocrine disruption. Expert panels used the Delphi method to make decisions on the strength of the data. RESULTS: Expert panels achieved consensus at least for probable (>20%) EDC causation for IQ loss and associated intellectual disability, autism, attention-deficit hyperactivity disorder, childhood obesity, adult obesity, adult diabetes, cryptorchidism, male infertility, and mortality associated with reduced testosterone. Accounting for probability of causation and using the midpoint of each range for probability of causation, Monte Carlo simulations produced a median cost of euro157 billion (or $209 billion, corresponding to 1.23% of EU gross domestic product) annually across 1000 simulations. Notably, using the lowest end of the probability range for each relationship in the Monte Carlo simulations produced a median range of euro109 billion that differed modestly from base case probability inputs. CONCLUSIONS: EDC exposures in the EU are likely to contribute substantially to disease and dysfunction across the life course with costs in the hundreds of billions of Euros per year. These estimates represent only those EDCs with the highest probability of causation; a broader analysis would have produced greater estimates of burden of disease and costs.

INTRODUCTION: Increasing evidence suggests that endocrine-disrupting chemicals (EDCs) contribute to male reproductive diseases and disorders. PURPOSE: To estimate the incidence/prevalence of selected male reproductive disorders/diseases and associated economic costs that can be reasonably attributed to specific EDC exposures in the European Union (EU). METHODS: An expert panel evaluated evidence for probability of causation using the Intergovernmental Panel on Climate Change weight-of-evidence characterization. Exposure-response relationships and reference levels were evaluated, and biomarker data were organized from carefully identified studies from the peer-reviewed literature to represent European exposure and approximate burden of disease as it occurred in 2010. The cost-of-illness estimation utilized multiple peer-reviewed sources. RESULTS: The expert panel identified low epidemiological and strong toxicological evidence for male infertility attributable to phthalate exposure, with a 40-69% probability of causing 618 000 additional assisted reproductive technology procedures, costing euro4.71 billion annually. Low epidemiological and strong toxicological evidence was also identified for cryptorchidism due to prenatal polybrominated diphenyl ether exposure, resulting in a 40-69% probability that 4615 cases result, at a cost of euro130 million (sensitivity analysis, euro117-130 million). A much more modest (0-19%) probability of causation in testicular cancer by polybrominated diphenyl ethers was identified due to very low epidemiological and weak toxicological evidence, with 6830 potential cases annually and costs of euro848 million annually (sensitivity analysis, euro313-848 million). The panel assigned 40-69% probability of lower T concentrations in 55- to 64-year-old men due to phthalate exposure, with 24 800 associated deaths annually and lost economic productivity of euro7.96 billion. CONCLUSIONS: EDCs may contribute substantially to male reproductive disorders and diseases, with nearly euro15 billion annual associated costs in the EU. These estimates represent only a few EDCs for which there were sufficient epidemiological studies and those with the highest probability of causation. These public health costs should be considered as the EU contemplates regulatory action on EDCs.

CONTEXT: Obesity and diabetes are epidemic in the European Union (EU). Exposure to endocrine-disrupting chemicals (EDCs) is increasingly recognized as a contributor, independent of diet and physical activity. OBJECTIVE: The objective was to estimate obesity, diabetes, and associated costs that can be reasonably attributed to EDC exposures in the EU. DESIGN: An expert panel evaluated evidence for probability of causation using weight-of-evidence characterization adapted from that applied by the Intergovernmental Panel on Climate Change. Exposure-response relationships and reference levels were evaluated for relevant EDCs, and biomarker data were organized from peer-reviewed studies to represent European exposure and burden of disease. Cost estimation as of 2010 utilized published cost estimates for childhood obesity, adult obesity, and adult diabetes. Setting, Patients and Participants, and Intervention: Cost estimation was performed from the societal perspective. RESULTS: The panel identified a 40% to 69% probability of dichlorodiphenyldichloroethylene causing 1555 cases of overweight at age 10 (sensitivity analysis: 1555-5463) in 2010 with associated costs of euro24.6 million (sensitivity analysis: euro24.6-86.4 million). A 20% to 39% probability was identified for dichlorodiphenyldichloroethylene causing 28 200 cases of adult diabetes (sensitivity analysis: 28 200-56 400) with associated costs of euro835 million (sensitivity analysis: euro835 million-16.6 billion). The panel also identified a 40% to 69% probability of phthalate exposure causing 53 900 cases of obesity in older women and euro15.6 billion in associated costs. Phthalate exposure was also found to have a 40% to 69% probability of causing 20 500 new-onset cases of diabetes in older women with euro607 million in associated costs. Prenatal bisphenol A exposure was identified to have a 20% to 69% probability of causing 42 400 cases of childhood obesity, with associated lifetime costs of euro1.54 billion. CONCLUSIONS: EDC exposures in the EU contribute substantially to obesity and diabetes, with a moderate probability of >euro18 billion costs per year. This is a conservative estimate; the results emphasize the need to control EDC exposures.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAH) are produced by the burning and processing of fuel oils, and have been associated with oxidant stress, insulin resistance and hypertension in adults. Few studies have examined whether adolescents are susceptible to cardiovascular effects of PAHs. OBJECTIVE: To study associations of PAH exposure with blood pressure (BP) and brachial artery distensibility (BAD), an early marker of arterial wall stiffness, in young boys attending three schools in Jeddah, Saudi Arabia in varying proximity to an oil refinery. METHODS: Air samples collected from the three schools were analyzed for PAHs. PAH metabolites (total hydroxyphenanthrenes and 1-hydroxypyrene) were measured in urine samples from 184 adolescent males, in whom anthropometrics, heart rate, pulse pressure, brachial artery distensibility and blood pressure were measured. Descriptive, bivariate and multivariable analyses were performed to assess relationships of school location and urinary PAH metabolites with cardiovascular measures. RESULTS: Total suspended matter was significantly higher (444+/-143mug/m(3)) at the school near the refinery compared to a school located near a ring road (395+/-65mug/m(3)) and a school located away from vehicle traffic (232+/-137mug/m(3)), as were PAHs. Systolic (0.47 SD units, p=0.006) and diastolic (0.53 SD units, p<0.001) BP Z-scores were highest at the school near the refinery, with a 4.36-fold increase in prehypertension (p=0.001), controlling for confounders. No differences in pulse pressure, BAD and heart rate were noted in relationship to school location. Urinary total hydroxyphenanthrenes and 1-hydroxypyrene were not associated with cardiovascular outcomes. CONCLUSIONS: Proximity to an oil refinery in Saudi Arabia is associated with prehypertension and increases in PAH and particulate matter exposures. Further study including insulin resistance measurements, better control for confounding, and longitudinal measurement is indicated.

Many women of reproductive age in the United States are marginally iodine deficient, perhaps because the salt in processed foods is not iodized. Iodine deficiency, per se, can interfere with normal brain development in their offspring; in addition, it increases vulnerability to the effects of certain environmental pollutants, such as nitrate, thiocyanate, and perchlorate. Although pregnant and lactating women should take a supplement containing adequate iodide, only about 15% do so. Such supplements, however, may not contain enough iodide and may not be labeled accurately. The American Thyroid Association recommends that pregnant and lactating women take a supplement with adequate iodide. The American Academy of Pediatrics recommends that pregnant and lactating women also avoid exposure to excess nitrate, which would usually occur from contaminated well water, and thiocyanate, which is in cigarette smoke. Perchlorate is currently a candidate for regulation as a water pollutant. The Environmental Protection Agency should proceed with appropriate regulation, and the Food and Drug Administration should address the mislabeling of the iodine content of prenatal/lactation supplements.