Aortic Elasticity and Arsenic Exposure: A Step Function rather than a Linear Function.

While the dose-response relationship for the carcinogenic effects of arsenic exposure indicates nonlinearity with increases only above about 150 µg/L arsenic in drinking water, similar analyses of noncarcinogenic effects of arsenic exposure remain to be conducted. We present here an alternative analysis of data on a measure of aortic elasticity, a risk factor for hypertension, and its relationship to urinary arsenic levels. An occupational health study from Ankara, Turkey by Karakulak et al. compared urinary arsenic levels and a measure of aortic elasticity (specifically, aortic strain) in workers with a linear no-threshold model.  We have examined these data with three alternative models-a fitted step-function, a stratified, and a weighted linear regression model. Discontinuity within the data revealed two subsets of data, one for workers with urinary arsenic levels ≤ 160 µg/L whose mean aortic strain level was 11.3% and one for workers with arsenic levels > 160 µg/L whose mean aortic stain level was 5.33 % (p < 0.0001). Several alternative models were examined that indicated the best model to be the threshold model with a threshold at a urinary arsenic level of 160 µg/L. Observation of a discontinuity in the data revealed their better fit to a threshold model (at a urinary arsenic level of 160 µg/L) than to a linear-no threshold model.  Examinations with alternative models are recommended for studies of arsenic and hypertension and possibly other noncarcinogenic effects.

Are residents of mountain-top mining counties more likely to have infants with birth defects? The West Virginia experience.

BACKGROUND: Pooled 1996 to 2003 birth certificate data for four central states in Appalachia indicated higher rates of infants with birth defects born to residents of counties with mountain-top mining (MTM) than born to residents of non-mining-counties (Ahern 2011). However, those analyses did not consider sources of uncertainty such as unbalanced distributions or quality of data. Quality issues have been a continuing problem with birth certificate analyses. We used 1990 to 2009 live birth certificate data for West Virginia to reassess this hypothesis. METHODS: Forty-four hospitals contributed 98% of the MTM-county births and 95% of the non-mining-county births, of which six had more than 1000 births from both MTM and nonmining counties. Adjusted and stratified prevalence rate ratios (PRRs) were computed both by using Poisson regression and Mantel-Haenszel analysis. RESULTS: Unbalanced distribution of hospital births was observed by mining groups. The prevalence rate of infants with reported birth defects, higher in MTM-counties (0.021) than in non-mining-counties (0.015), yielded a significant crude PRR (cPRR = 1.43; 95% confidence interval [CI] = 1.36-1.52) but a nonsignificant hospital-adjusted PRR (adjPRR = 1.08; 95% CI = 0.97-1.20; p = 0.16) for the 44 hospitals. So did the six hospital data analysis ([cPRR = 2.39; 95% CI = 2.15-2.65] and [adjPRR = 1.01; 95% CI, 0.89-1.14; p = 0.87]). CONCLUSION: No increased risk of birth defects was observed for births from MTM-counties after adjustment for, or stratification by, hospital of birth. These results have consistently demonstrated that the reported association between birth defect rates and MTM coal mining was a consequence of data heterogeneity. The data do not demonstrate evidence of a "Mountain-top Mining" effect on the prevalence of infants with reported birth defects in WV.

The influence of misclassification bias on the reported rates of congenital anomalies on the birth certificates for West Virginia--a consequence of an open-ended query.

BACKGROUND: Passive surveillance for congenital anomalies using birth certificates are generally considered to have biased reporting, though the sources of those biases are not well-known nor controlled for. We have analyzed the congenital anomaly reporting data for 418,385 live births in West Virginia (1990-2009) from the 1989 US standard birth certificate and have newly identified a particular source of bias. METHODS: Congenital anomaly prevalence rates per 100 live births have been determined for both specified birth defects and for other congenital anomalies by county, by hospital, and by year. Extreme outliers were identified by z score. Text strings for "other congenital anomaly" reports recorded for 1998-2009 were assessed for information on congenital anomalies. RESULTS: While rates for specified birth defects reported in checked-box format showed little variation, rates for "other congenital anomaly" collected in open-ended format showed much variation. Nearly half of the "other congenital anomaly" reports were for neonatal conditions rather than for major structural congenital anomalies. This misclassification alone had elevated the state-wide congenital anomaly reporting rate from 1.1 to 1.8% of live births. Geographic clustering and a temporal bulge in congenital anomaly reports disappeared after misclassified data were removed. CONCLUSIONS: Data collected in checked-box format on specified birth defects showed consistent patterns over time and space, while data collected in open-ended format on "other congenital anomalies" showed an epidemiological pattern reflecting neonatal conditions rather than birth defects. The 2003 US standard birth certificate wisely limits data collection to specified birth defects using the checked-box format.

Bladder/lung cancer mortality in Blackfoot-disease (BFD)-endemic area villages with low (<150 µg/L) well water arsenic levels--an exploration of the dose-response Poisson analysis.

OBJECTIVE: To examine the analytic role of arsenic exposure on cancer mortality among the low-dose (well water arsenic level <150 µg/L) villages in the Blackfoot-disease (BFD) endemic area of southwest Taiwan and with respect to the southwest regional data. METHOD: Poisson analyses of the bladder and lung cancer deaths with respect to arsenic exposure (µg/kg/day) for the low-dose (<150 µg/L) villages with exposure defined by the village median, mean, or maximum and with or without regional data. RESULTS: Use of the village median well water arsenic level as the exposure metric introduced misclassification bias by including villages with levels >500 µg/L, but use of the village mean or the maximum did not. Poisson analyses using mean or maximum arsenic levels showed significant negative cancer slope factors for models of bladder cancers and of bladder and lung cancers combined. Inclusion of the southwest Taiwan regional data did not change the findings when the model contained an explanatory variable for non-arsenic differences. A positive slope could only be generated by including the comparison population as a separate data point with the assumption of zero arsenic exposure from drinking water and eliminating the variable for non-arsenic risk factors. CONCLUSION: The cancer rates are higher among the low-dose (<150 µg/L) villages in the BFD area than in the southwest Taiwan region. However, among the low-dose villages in the BFD area, cancer risks suggest a negative association with well water arsenic levels. Positive differences from regional data seem attributable to non-arsenic ecological factors.

A review of low-dose arsenic risks and human cancers.

The linear no-threshold (LNT) model has historically been the default assumption in assessing carcinogenic risk from arsenic ingestion based on epidemiological studies. This contrasts with the threshold model used in assessing carcinogenic risk from arsenic ingestion derived from toxicological investigations of experimental animals. We present here a review of our epidemiological work that has examined models that may better explain the human cancer risk from the ingestion of arsenic, particularly from low level exposures, than does the LNT model. While previous epidemiology studies have demonstrated increased risks of bladder, lung, and skin cancers at arsenic exposures of 200 ug/L or greater, we seek here to examine the dose-response patterns at lower exposure levels. These include ecological, case/control, and cohort designs. Methodologic issues include choice of continuous or stratified analysis of exposure data, search for sources of non-conformity or variability, and distinctions in water sources and geography. Multiple studies have yielded useful data-based models, including threshold models, hockey-stick models, and "J-shaped" linear-quadratic models. These models have found that increased cancer risk may only begin at specific arsenic exposure levels greater than zero. These results provide guidance in seeking toxicological explanations and public health reference levels.

Prostate Cancer Incidence in U.S. Counties and Low Levels of Arsenic in Drinking Water.

Background: Although inorganic arsenic in drinking water at high levels (100s-1000s µg/L [ppb]) increases cancer risk (skin, bladder, lung, and possibly prostate), the evidence at lower levels is limited. Methods: We conducted an ecologic analysis of the dose-response relationship between prostate cancer incidence and low arsenic levels in drinking water in a large study of U.S. counties (N = 710). County arsenic levels were <200 ug/L with median <100 ug/L and dependency greater than 10%. Groundwater well usage, water arsenic levels, prostate cancer incidence rates (2009-2013), and co-variate data were obtained from various U.S. governmental agencies. Poisson and negative-binomial regression analyses and stratified analysis were performed. Results: The best fitting polynomial analysis yielded a J-shaped linear-quadratic model. Linear and quadratic terms were significant (p < 0.001) in the Poisson model, and the quadratic term was significant (p < 0.05) in the negative binomial model. This model indicated a decreasing risk of prostate cancer with increasing arsenic level in the low range and increasing risk above. Conclusions: This study of prostate cancer incidence in US counties with low levels of arsenic in their well-water arsenic levels finds a j-shaped model with decreasing risk at very low levels and increasing risk at higher levels.

Maternal tobacco use: A third-trimester risk factor for small-for-gestational-age pregnancy outcome.

BACKGROUND: Small for gestational age (SGA) is a well-known consequence of maternal smoking. Here, we newly examine the magnitude of SGA risk by week of gestational age. METHODS: Singleton live births (N = 3,032,928) with recorded birth weight, gestational age (22-44 weeks), and maternal tobacco use (Y/N) were categorized as to SGA (Y/N), based on 10th percentile gender-specific weights-for-age. RESULTS: SGA prevalence among tobacco users (19.5%) and non-users (9.1%) yielded a significant SGA prevalence rate ratio of 2.15 (2.13-2.16) and a significant adjusted odds ratio of 2.36 (2.34-2.38). The tobacco non-users' rate was steadily near 9% across the week 22-44 gestational age range. The tobacco users' rate was steady until week 33 when it rose monotonically through week 37 to about 20% at week 38 and remained high. This pattern for SGA by gestational week was similar for prevalence rates and adjusted ORs. Tobacco use only through week 33 was not seen to be an SGA risk factor. The magnitude of tobacco use as an SGA risk factor for late third trimester births increased during the period of preterm birth and became fully evident with a two-fold risk for full term infants. CONCLUSION: We newly report the temporal pattern of tobacco-related SGA by week of gestational age. Tobacco-related SGA was only seen for late third trimester births - increasing during weeks 33-37 with a doubling during weeks 38-44. This pattern, informative for issues of mechanism, highlights the potential benefit of extending tobacco cessation programs through the third trimester of pregnancy.

Assessment of developmental risk information on medicines for inclusion on the WHO's Essential Medicines List.

BACKGROUND: The WHO develops biannually an Essential Medicines List (EML) of medications proposed for national formularies to be safe, effective and cost-effective. This satisfies the priority healthcare needs of most adult populations, but it does not consider the unique toxicological risks that occur from exposures during pregnancy. METHODS: Developmental toxicity risk information for the 451 specific agents on the 2017 EML were identified from four well-recognized compendia of teratological assessments. On this basis, each agent was classified as having known, suggested, or little to no developmental risk, or as having insufficient information. RESULTS: Thirteen (3%) EML agents posed known developmental risks, and 115 (25%) had evidence suggesting risk. For 170 (38%) agents, there was little or no evidence of such risk. Thus, risk classification could be determined for 66% of the agents. For an additional 153 (34%) agents, the information was insufficient for classification. CONCLUSION: It is feasible to expand the classification of most of the EML agents to include the risks from exposure during pregnancy.

Arsenic exposure and childhood cancer--a systematic review of the literature.

The literature on environmental arsenic exposure and childhood cancer risk comprises 1) studies seeking childhood cancers among arsenic-exposed populations, 2) studies seeking arsenic exposure among childhood cancer cases, and 3) studies seeking associations in populations with both arsenic exposures and childhood cancer cases. No skin cancers were found in dermal examinations of over 25,000 children in Southwest Taiwan or West Bengal, India, with high drinking-water arsenic levels. Childhood cancer types were not different for those living near a Swedish smelter. In Montreal, Canada, children with acute lymphoblastic leukemia did not have drinking-water arsenic more frequently either prenatal or postnatal, and British children with cancer did not have early exposure to environmental sources of airborne arsenic. Neither hair arsenic levels in Woburn, Massachusetts, nor water arsenic levels in Fallon, Nevada, were elevated for children with leukemia. The literature, while limited, does not seem to support an association between arsenic exposure and childhood cancers.

Lung Cancer Risk and Low (≤50 µg/L) Drinking Water Arsenic Levels for US Counties (2009⁻2013)-A Negative Association.

While epidemiologic studies clearly demonstrate drinking water with high levels of arsenic as a significant risk factor for lung cancer, the evidence at low levels (≤50 µg/L) is uncertain. Therefore, we have conducted an ecological analysis of recent lung cancer incidence for US counties with a groundwater supply of.

Arsenic cancer risk confounder in southwest Taiwan data set.

Quantitative analysis for the risk of human cancer from the ingestion of inorganic arsenic has been based on the reported cancer mortality experience in the blackfoot disease (BFD) -endemic area of southwest Taiwan. Linear regression analysis shows that arsenic as the sole etiologic factor accounts for only 21% of the variance in the village standardized mortality ratios for bladder and lung cancer. A previous study had reported the influence of confounders (township, BFD prevalence, and artesian well dependency) qualitatively, but they have not been introduced into a quantitative assessment. In this six-township study, only three townships (2, 4, and 6) showed a significant positive dose-response relationship with arsenic exposure. The other three townships (0, 3, and 5) demonstrated significant bladder and lung cancer risks that were independent of arsenic exposure. The data for bladder and lung cancer mortality for townships 2, 4, and 6 fit an inverse linear regression model (p < 0.001) with an estimated threshold at 151 microg/L (95% confidence interval, 42 to 229 microg/L) . Such a model is consistent with epidemiologic and toxicologic literature for bladder cancer. Exploration of the southwest Taiwan cancer mortality data set has clarified the dose-response relationship with arsenic exposure by separating out township as a confounding factor. Key words: arsenic, blackfoot disease, bladder cancer, cancer risk, confounder, dose-response relationship, southwest Taiwan, threshold model.

Arsenic in Drinking Water and Lung Cancer Mortality in the United States: An Analysis Based on US Counties and 30 Years of Observation (1950-1979).

Background. To examine whether the US EPA (2010) lung cancer risk estimate derived from the high arsenic exposures (10-934 µg/L) in southwest Taiwan accurately predicts the US experience from low arsenic exposures (3-59 µg/L). Methods. Analyses have been limited to US counties solely dependent on underground sources for their drinking water supply with median arsenic levels of ≥3 µg/L. Results. Cancer risks (slopes) were found to be indistinguishable from zero for males and females. The addition of arsenic level did not significantly increase the explanatory power of the models. Stratified, or categorical, analysis yielded relative risks that hover about 1.00. The unit risk estimates were nonpositive and not significantly different from zero, and the maximum (95% UCL) unit risk estimates for lung cancer were lower than those in US EPA (2010). Conclusions. These data do not demonstrate an increased risk of lung cancer associated with median drinking water arsenic levels in the range of 3-59 µg/L. The upper-bound estimates of the risks are lower than the risks predicted from the SW Taiwan data and do not support those predictions. These results are consistent with a recent metaregression that indicated no increased lung cancer risk for arsenic exposures below 100-150 µg/L.

Cardiovascular Effects of the New Weight Loss Agents.

The global obesity epidemic and its impact on cardiovascular outcomes is a topic of ongoing debate and investigation in the cardiology community. It is well known that obesity is associated with multiple cardiovascular risk factors. Although life-style changes are the first line of therapy, they are often insufficient in achieving weight loss goals. Liraglutide, naltrexone/bupropion, and phentermine/topiramate are new agents that have been recently approved to treat obesity, but their effects on cardiovascular risk factors and outcomes are not well described. This review summarizes data currently available for these novel agents regarding drug safety, effects on major cardiovascular risk factors, impact on cardiovascular outcomes, outcomes research that is currently in progress, and areas of uncertainty. Given the impact of obesity on cardiovascular health, there is a pressing clinical need to understand the effects of these agents beyond weight loss alone.

The effect of perchlorate, thiocyanate, and nitrate on thyroid function in workers exposed to perchlorate long-term.

Perchlorate (ClO(4)(-)) and thiocyanate (SCN(-)) are potent and nitrate (NO(3)(-)) a weak competitive inhibitor of the thyroid sodium-iodide symporter. To determine the effects of long-term, high ClO(4)(-) exposure on thyroid function, we conducted a study of 29 workers employed for at least 1.7 yr (50% over 5.9 yr) in an ammonium ClO(4)(-) production plant in Utah. Serum ClO(4)(-), SCN(-), and NO(3)(-); serum T(4), free T(4) index, total T(3), thyroglobulin (Tg), and TSH; 14-h thyroid radioactive iodine uptake (RAIU); and urine iodine (I) and ClO(4)(-) were assessed after 3 d off (Pre) and during the last of three 12-h night shifts in the plant (During) and in 12 volunteers (C) not working in the plant. Serum and urine ClO(4)(-) were not detected in C; urine ClO(4)(-) was not detected in 12 of 29 and was 272 microg/liter in 17 Pre workers; serum ClO(4)(-) was not detected in 27 of 29 Pre; and serum and urine ClO(4)(-) were markedly elevated during ClO(4)(-) exposure to 868 microg/liter and 43 mg/g creatinine, respectively. Serum SCN(-) and NO(3)(-) concentrations were similar in all groups. Thyroid RAIUs were markedly decreased in During compared with Pre (13.5 vs. 21.5%; P < 0.01, paired t) and were associated with an increase in urine I excretion (230 vs. 148 microg I/g Cr; P = 0.02, paired t) but were similar to those in the C group (14.4%). Serum TSH and Tg concentrations were normal and similar in the three groups. Serum T(4) (8.3 vs. 7.7 microg/dl), free T(4) index (2.4 vs. 2.2), and total T(3) (147 vs. 134 ng/dl) were slightly but significantly increased in the During vs. Pre workers (P < 0.01, paired t). Thyroid volumes and patterns by ultrasound were similar in the 29 workers and 12 community volunteers. In conclusion, high ClO(4)(-) absorption during three nights work exposure decreased the 14-h thyroid RAIU by 38% in ClO(4)(-) production workers compared with the RAIU after 3 d off. However, serum TSH and Tg concentrations and thyroid volume by ultrasound were not affected by ClO(4)(-), suggesting that long-term, intermittent, high exposure to ClO(4)(-) does not induce hypothyroidism or goiter in adults.

A Systematic Review and Meta-Regression Analysis of Lung Cancer Risk and Inorganic Arsenic in Drinking Water.

High levels (> 200 µg/L) of inorganic arsenic in drinking water are known to be a cause of human lung cancer, but the evidence at lower levels is uncertain. We have sought the epidemiological studies that have examined the dose-response relationship between arsenic levels in drinking water and the risk of lung cancer over a range that includes both high and low levels of arsenic. Regression analysis, based on six studies identified from an electronic search, examined the relationship between the log of the relative risk and the log of the arsenic exposure over a range of 1-1000 µg/L. The best-fitting continuous meta-regression model was sought and found to be a no-constant linear-quadratic analysis where both the risk and the exposure had been logarithmically transformed. This yielded both a statistically significant positive coefficient for the quadratic term and a statistically significant negative coefficient for the linear term. Sub-analyses by study design yielded results that were similar for both ecological studies and non-ecological studies. Statistically significant X-intercepts consistently found no increased level of risk at approximately 100-150 µg/L arsenic.

Newborn thyroxine levels and childhood ADHD.

OBJECTIVES: Normal brain development is highly dependent on adequate levels of iodine and thyroid hormone. It has been suggested that Attention Deficit Hyperactivity Disorder (ADHD) is the consequence of prenatal thyroidal endocrine disruption. The hypothesis was examined using neonatal thyroxine levels as a bio-marker of prenatal thyroid status and comparing it to subsequent development of ADHD. DESIGN AND METHODS: In a matched case-control study, cases were defined as children diagnosed with ADHD, while children born in the same hospital and tested on the same day served as matched controls. Conditional logistic regression analysis with unequal numbers of controls was performed. RESULTS: The neonatal thyroxine levels were within normal limits for each of the children who were subsequently diagnosed as having ADHD, and their distribution was no different from that of their controls. CONCLUSIONS: Children diagnosed with ADHD do not demonstrate prenatal thyroidal dysfunction as reflected in the newborn thyroxine levels, therefore neonatal thyroxine levels are not a bio-marker for the subsequent development of ADHD.

Lack of a relation between human neonatal thyroxine and pediatric neurobehavioral disorders.

The growth and differentiation of the central nervous system are closely related to the presence of iodine and thyroid hormones. It has been hypothesized that neurobehavioral disabilities of childhood, such as attention deficit hyperactivity disorder (ADHD), learning disorders, and autism can be attributed to fetal thyroidal endocrine disruption in utero. To determine whether there is an association between neonatal thyroid status and a subsequent diagnosis of a neurobehavioral disability, neonatal thyroxine (T(4)) levels have been used as the indicator of the presence of intrauterine thyroidal dysfunction. Neonatal T(4) levels were obtained from the neonatal hypothyroidism screening program. All cases were diagnosed at medical school diagnostic clinics, the diagnostic categories being ADHD, autism spectrum disorder, behavioral disorder, cognitive disorder, developmental delay, emotional disorder, learning disability, and speech/language disorder. Conditional logistic regression analysis was performed for each clinical condition. Odds ratios for the conditions ranged from 0.92 to 1.13 with p values ranging between 0.19 and 0.84. No significant differences were detected between neonatal T(4) values of the cases and the controls for any of the neurobehavioral conditions. All neonatal T(4) values were within normal ranges. The data provide no evidence to suggest that intrauterine thyroid status as reflected by the neonatal T(4) values had an impact on the neurologic disorders diagnosed in childhood.

Arsenic in drinking water and bladder cancer mortality in the United States: an analysis based on 133 U.S. counties and 30 years of observation.

This study analyzes the relationship between arsenic exposure through drinking water and bladder cancer mortality. The county-specific white male bladder cancer mortality data (1950-1979) and county-specific groundwater arsenic concentration data were obtained for 133 U.S. counties known to be exclusively dependent on groundwater for their public drinking water supply. No arsenic-related increase in bladder cancer mortality was found over the exposure range of 3 to 60 microg/L using stratified analysis and regression analyses (both unweighted and weighted by county population and using both mean and median arsenic concentrations). These results, which provide a direct estimate of arsenic-related cancer risk for U.S. residents, exclude the National Research Council's 2001 risk estimate that was based on Southwest Taiwan data and required adjusting for differences between the body mass and water consumption rates of U.S. and Taiwanese residents.