Hypertension and chronic kidney disease: controversies in pathogenesis and treatment.

The relationship between hypertension and chronic kidney disease (CKD) has long been the subject of controversy. The pathogenetic mechanisms of nephropathy in non-diabetic individuals with hypertension, as well as optimal hypertension treatment targets in populations with nephropathy remain important clinical concerns. This manuscript reviews breakthroughs in molecular genetics that have clarified the complex relationship between hypertension and kidney disease, answering the question of which factor comes first. An overview of the potential roles that hyperuricemia plays in the pathogenesis of hypertension and CKD and current blood pressure treatment guidelines in populations with CKD are discussed. The ongoing National Institutes of Health-sponsored Systolic Blood Pressure Intervention Trial (SPRINT) is underway to help answer these important questions. Enrollment of 9250 hypertensive SPRINT participants will be completed in 2013; important results on ideal blood pressure control targets for reducing nephropathy progression, cardiovascular disease end-points, and preserving cognitive function are expected. As such, many of the controversial aspects of hypertension management will likely be clarified in the near future.

Levels of seven urinary phthalate metabolites in a human reference population.

Using a novel and highly selective technique, we measured monoester metabolites of seven commonly used phthalates in urine samples from a reference population of 289 adult humans. This analytical approach allowed us to directly measure the individual phthalate metabolites responsible for the animal reproductive and developmental toxicity while avoiding contamination from the ubiquitous parent compounds. The monoesters with the highest urinary levels found were monoethyl phthalate (95th percentile, 3,750 ppb, 2,610 microg/g creatinine), monobutyl phthalate (95th percentile, 294 ppb, 162 microg/g creatinine), and monobenzyl phthalate (95th percentile, 137 ppb, 92 microg/g creatinine), reflecting exposure to diethyl phthalate, dibutyl phthalate, and benzyl butyl phthalate. Women of reproductive age (20-40 years) were found to have significantly higher levels of monobutyl phthalate, a reproductive and developmental toxicant in rodents, than other age/gender groups (p < 0.005). Current scientific and regulatory attention on phthalates has focused almost exclusively on health risks from exposure to only two phthalates, di-(2-ethylhexyl) phthalate and di-isononyl phthalate. Our findings strongly suggest that health-risk assessments for phthalate exposure in humans should include diethyl, dibutyl, and benzyl butyl phthalates.

Comparison of serum and salivary cotinine measurements by a sensitive high-performance liquid chromatography-tandem mass spectrometry method as an indicator of exposure to tobacco smoke among smokers and nonsmokers.

Exposure to tobacco smoke, both from active smoking and from passive exposure to environmental tobacco smoke, can be monitored by measuring cotinine, a metabolite of nicotine, in a variety of biological sources including blood, urine, and saliva. Previously, a sensitive atmospheric-pressure ionization, tandem mass spectrometric (LC-API-MS-MS) method for cotinine measurements in serum was developed in support of a large, recurrent national epidemiologic investigation. The current study examined the application of this LC-API-MS-MS method to both serum and saliva cotinine measurements in a group of 200 healthy adults, including both smokers and nonsmokers. The primary objective of this study was to evaluate the relationship between serum and saliva cotinine concentrations to facilitate the linking of results from epidemiologic studies using salivary cotinine measurements to existing national data based on serum cotinine analyses. The results indicate that a simple, linear relationship can be developed to describe serum and saliva cotinine concentrations in an individual, and the expression describing this relationship can be used to estimate with reasonable accuracy (approximately +/- 10%) the serum cotinine concentration in an individual given his or her salivary cotinine result. It was further confirmed that saliva cotinine samples are generally quite stable during storage after collection, even at ambient temperatures, and this sample matrix appears to be well-suited to the requirements of many epidemiologic investigations.

Measuring secondhand smoke exposure in babies: the reliability and validity of mother reports in a sample of low-income families.

The reliability and validity of mother's reports of their infants' exposure to secondhand smoke (SHS) were examined in an ethnically diverse sample of low-income, low-education families (N = 141 mothers). At baseline and posttest, smoking mothers reported about their infants' SHS exposure at different locations and by different sources during the previous week. Findings show that mothers can give reliable accounts of the degree to which they contribute to their babies' SHS exposure. Mothers are able to differentiate between their own smoking behavior and the extent to which they expose their infants. Consistent with the overall exposure pattern, exposure caused by the mother and exposure occurring at home showed the strongest associations with biological and environmental measures. These findings suggest that smoking mothers can provide reliable and valid reports of the degree to which their infants are exposed to SHS.

Exposure of the U.S. population aged 6 years and older to cadmium: 1988-1994.

Cadmium was measured in urine specimens from 22,162 participants in the Third National Health and Nutrition Examination Survey (NHANES III 1988-1994). Urine cadmium, expressed either as uncorrected (microg/L) or creatinine corrected (microg/g creatinine) increased with age and with smoking. The arithmetic mean value for urine cadmium in the U.S. population was 0.57 microg/L or 0.48 microg/g creatinine. Based on our estimates, about 2.3% of the U.S. population have urine cadmium concentrations greater than 2 microg/g creatinine, and 0.2% have concentrations greater than 5 microg/g creatinine, the current World Health Organization health-based exposure limit.

Measuring environmental tobacco smoke exposure in infants and young children through urine cotinine and memory-based parental reports: empirical findings and discussion.

OBJECTIVE: This study examined the reliability and potential biases of two urine collection methods from which cotinine measures were obtained and the validity of memory-based parental reports of their children's exposure to environmental tobacco smoke (ETS). DESIGN: Structured interviews were conducted with mothers of infants and young children to obtain memory-based estimates of recent ETS exposure. Urine samples were collected through standard and cotton roll collection methods for cotinine analysis. SETTING: All interviews took place at an off-campus research facility. Urine samples were collected at the study office or the subjects' homes. PARTICIPANTS: Mothers were recruited from San Diego county sites of the Women, Infants, and Children (WIC) Supplemental Food and Nutrition Program. Sample 1 (infants) consisted of eight boys and eight girls aged 1-44 months (mean = 12.6 months). Sample 2 (children) included 10 boys and 10 girls aged 3-8 years (mean = 61.2 months). MAIN OUTCOME MEASURES: Urine cotinine and memory-based parent reports of ETS exposure from structured interviews. RESULTS: There was overall high reliability for urine cotinine measures and no effect of collection method on urine cotinine levels. Memory-based reports obtained from smoking mothers showed moderately strong and consistent linear relationships with urine cotinine measures of their infants and children (r = 0.50 to r = 0.63), but not for reports obtained from non-smoking mothers. CONCLUSIONS: Memory-based parental reports of short-term ETS exposure can play an important role in quantifying ETS exposure in infants and children.

Reference range concentrations of N-acetyl-S-(2-hydroxyethyl)-L-cysteine, a common metabolite of several volatile organic compounds, in the urine of adults in the United States.

N-acetyl-S-(2-hydroxyethyl)-L-cysteine (2-hydroxyethyl mercapturic acid, HEMA) is a urinary metabolite of several hazardous chemicals, including vinyl chloride (VC), ethylene oxide (EO), and ethylene dibromide (EDB). Information about the levels of HEMA in the general population is useful for assessing human exposures to HEMA parent compounds, including VC, EO, and EDB. To establish reference range concentrations for HEMA, we analyzed urine samples from 412 adult participants in the Third National Health and Nutrition Examination Survey (NHANES II) by using isotope-dilution high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). HEMA was detected in 71% of the samples examined. Creatinine-corrected concentrations ranged from less than 0.68 microg/g creatinine to 58.7 microg/g creatinine; the 95th percentile concentration was 11.2 microg/g creatinine; and the geometric mean and median creatinine-corrected concentrations were both 1.6 microg/g creatinine. We observed a statistically significant difference (P=0.0001) in the creatinine-corrected geometric mean concentration values of HEMA between smokers (2.8 microg/g creatinine) and nonsmokers (1.1 microg/g creatinine). The high levels of HEMA seen among smokers likely originated from HEMA-producing chemicals known to be present in tobacco smoke.

Uranium and thorium in urine of United States residents: reference range concentrations.

We measured uranium and thorium in urine of 500 U. S. residents to establish reference range concentrations using a magnetic-sector inductively coupled argon plasma mass spectrometer (ICP-MS). We found uranium at detectable concentrations in 96.6% of the urine specimens and thorium in 39.6% of the specimens. The 95th percentile concenetration for uranium was 34.5 ng/L (parts per trillion); concentrations ranged up to 4080 ng/L. Thorium had a 95th percentile concentration of 3.09 ng/L; concentrations ranged up to 7.7 ng/L.

Evaluation of four maternal smoking questions.

OBJECTIVE: The authors evaluated four questions about maternal smoking during pregnancy for use on birth certificates. METHODS: Question 1 (yes/no format) and Question 2 (trimester-specific design) were tested among 1171 women who delivered at two Kaiser Permanente medical centers in northern California. Responses to Questions 1 and 2 were compared with smoking information provided by participants in telephone interviews conducted during pregnancy. Question 3 (multiple choice format) and Question 4 (month- and grouped month-specific design) were tested among 900 women who enrolled in a statewide prenatal screening program and who delivered in 20 hospitals in four Central Valley counties. Responses to Questions 3 and 4 were compared with mid-pregnancy serum cotinine levels. The authors evaluated the four questions in terms of conciseness, response rate, data accuracy, and type of data requested. RESULTS: Questions 1 and 2 were the most concise. Response rates could not be calculated for Questions 1 and 2. Response rates were 86.0% for Question 3 and 74.2% for Question 4. Sensitivity was 47.3% for Question 1, 62.1% for Question 2, 83.8% for Question 3, and 86.7% for Question 4. The types of data requested by Questions 2 and 4 seem to best satisfy the needs of the broad audience of birth certificate users. CONCLUSIONS: No single question was clearly superior. The authors propose a combination of Questions 2 and 4, which asks about average number of cigarettes smoked per day in the three months before pregnancy and in each trimester of pregnancy.

Current activities at the Centers for Disease Control and Prevention's National Diabetes Laboratory.

In 1997, the Centers for Disease Control and Prevention established the National Diabetes Laboratory in order to help prevent and treat type 1 diabetes. This state-of-the-art laboratory collaborates with research scientists and key national and international organizations throughout the world to identify and study risk factors for type 1 diabetes by developing measurements for glycosylated proteins, developing and evaluating technology for measuring genetic risk factors for the disease, and working to standardize autoantibody measurements. Developing improved technologies for diagnosing and managing diabetes and developing reference materials for properly calibrating and standardizing blood glucose meters are also critical aspects of the laboratory's work. In addition, the laboratory provides quality storage for valuable collections of biologics and other materials and facilitates sharing of specimens, associated epidemiologic data, and test results. Working with our partners in diabetes research, we are improving the diagnosis, treatment, and prevention of type 1 diabetes.

Exposure of the U.S. population to lead, 1991-1994.

Blood lead measurements were obtained on 13,642 persons aged 1 year and older who participated in Phase 2 of the Third National Health and Nutrition Examination Survey (NHANES III) from 1991 through 1994. NHANES III is a national representative survey of the civilian, noninstitutionalized U.S. population. The overall mean blood lead level for the U.S. population aged 1 year and older was 2.3 microgram/dl, with 2.2% of the population having levels >=10 microgram/dl, the level of health concern for children. Among U.S. children aged 1-5 years, the mean blood lead level was 2.7 microgram/dl, and 890,000 of these children (4.4%) had elevated blood lead levels. Sociodemographic factors associated with higher blood lead levels in children were non-Hispanic black race/ethnicity, low income, and residence in older housing. The prevalence of elevated blood lead levels was 21.9% among non-Hispanic black children living in homes built before 1946 and 16.4% among children in low-income families who lived in homes built before 1946. Blood lead levels continue to decline in the U.S. population, but 890,000 children still have elevated levels. Public health efforts have been successful in removing lead from population-wide sources such as gasoline and lead-soldered food and drink cans, but new efforts must address the difficult problem of leaded paint, especially in older houses, as well as lead in dust and soil. Lead poisoning prevention programs should target high-risk persons, such as children who live in old homes, children of minority groups, and children living in families with low income.

Racial and ethnic differences in serum cotinine levels of cigarette smokers: Third National Health and Nutrition Examination Survey, 1988-1991.

CONTEXT: Cotinine, a metabolite of nicotine, is a marker of exposure to tobacco smoke. Previous studies suggest that non-Hispanic blacks have higher levels of serum cotinine than non-Hispanic whites who report similar levels of cigarette smoking. OBJECTIVE: To investigate differences in levels of serum cotinine in black, white, and Mexican American cigarette smokers in the US adult population. DESIGN: Third National Health and Nutrition Examination Survey, 1988-1991. PARTICIPANTS: A nationally representative sample of persons aged 17 years or older who participated in the survey. OUTCOME MEASURES: Serum cotinine levels by reported number of cigarettes smoked per day and by race and ethnicity. RESULTS: A total of 7182 subjects were involved in the study; 2136 subjects reported smoking at least 1 cigarette in the last 5 days. Black smokers had cotinine concentrations substantially higher at all levels of cigarette smoking than did white or Mexican American smokers (P<.001). Serum cotinine levels for blacks were 125 nmol/L (22 ng/mL) (95% confidence interval [CI], 79-176 nmol/L [14-31 ng/mL]) to 539 nmol/L (95 ng/mL) (95% CI, 289-630 nmol/L [51-111 ng/mL]) higher than for whites and 136 nmol/L (24 ng/mL) (95% CI, 85-182 nmol/L [15-32 ng/mL]) to 641 nmol/L (113 ng/mL) (95% CI, 386-897 nmol/L [68-158 ng/mL]) higher than for Mexican Americans. These differences do not appear to be attributable to differences in environmental tobacco smoke exposure or in number of cigarettes smoked. CONCLUSIONS: To our knowledge, this study provides the first evidence from a national study that serum cotinine levels are higher among black smokers than among white or Mexican American smokers. If higher cotinine levels among blacks indicate higher nicotine intake or differential pharmacokinetics and possibly serve as a marker of higher exposure to cigarette carcinogenic components, they may help explain why blacks find it harder to quit and are more likely to experience higher rates of lung cancer than white smokers.

Trace metals in urine of United States residents: reference range concentrations.

We measured 13 metals in the urine of 496 United States residents to establish reference range concentrations using inductively coupled argon plasma mass spectrometry and Zeeman graphite furnace atomic absorption spectrometry. We frequently found 8 of these analytes at detectable concentrations in urine specimens: molybdenum (in 99.8%); lead (98.8%); tin (89%); thallium (77%); antimony (73.5%); manganese (73%); cesium (71%); tungsten (70%); and platinum (69.7%). The 95th percentile concentration for molybdenum was 168 micrograms/L; concentrations ranged up to 688 micrograms/L. Lead concentrations ranged up to 67 micrograms/L, and the 95th upper percentile was 6.4 micrograms/L. Tin had 95th upper percentile of 20.1 micrograms/L. Other analytes measured at detectable concentrations included barium (in 67% of the specimens); beryllium (67%); chromium (54%); thorium (44%); and cobalt (43%). In almost every case, the 95th upper percentiles of these analytes were less than 15 micrograms/L.

Serum dioxin levels in Seveso, Italy, population in 1976.

On July 10, 1976, an explosion at a chemical plant near Seveso, Italy, released a mixture of chemicals, including 2,3,7,8-tetrachlorodibenzo-p-dioxin and 2,4,5-trichlorophenol. As a result, several thousand people in the Seveso area may have been exposed to those chemicals. At that time, human exposure assessment was based primarily on soil levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Medical examinations of this potentially exposed population and control subjects were begun in 1976 and in some cases continued until 1985. In 1988, we began assessing human exposure in this population by measuring 2,3,7,8-tetrachlorodibenzo-p-dioxin in small volumes of serum specimens remaining from the medical examinations. As expected, we found that the median serum dioxin levels were highest among people who lived closest to the explosion and were progressively lower among groups living farther away. These measurements have allowed us to assess exposure more accurately among individuals in this population and to relate exposure to various health effects. We found that some individuals in the exposed population had among the highest serum dioxin levels ever reported, yet chloracne was the only unequivocal effect found; cancer risks are still being investigated. We also found that other individuals with as high or higher serum dioxin levels did not develop chloracne. We also found that the serum half-life of dioxin in this population was 7-8 years, which agrees with other findings although we do report some differences in the serum half-life of TCDD for women and children. We also observed an increase in the percentage of female newborns to parents who resided in Zone A at the time of the explosion, and we also report on the 1976 serum dioxin levels in people who later developed cancer.

Development and validation of sensitive method for determination of serum cotinine in smokers and nonsmokers by liquid chromatography/atmospheric pressure ionization tandem mass spectrometry.

We describe a sensitive and specific method for measuring cotinine in serum by HPLC coupled to an atmospheric pressure chemical ionization tandem mass spectrometer. This method can analyze 100 samples/day on a routine basis, and its limit of detection of 50 ng/L makes it applicable to the analysis of samples from nonsmokers potentially exposed to environmental tobacco smoke. Analytical accuracy has been demonstrated from the analysis of NIST cotinine standards and from comparative analyses by both the current method and gas chromatography/high-resolution mass spectrometry. Precision has been examined through the repetitive analysis of a series of bench and blind QC materials. This method has been applied to the analysis of cotinine in serum samples collected as part of the Third National Health and Nutrition Examination Survey (NHANES III).

The reliability of the serum dioxin measurement in veterans of Operation Ranch Hand.

A study was conducted on the reliability of the serum dioxin measurement of enlisted Ranch Hands veterans participating in the Air Force Health Study using paired serum dioxin measurements. The 46 veterans were not randomly selected, but their demographic characteristics, health, and dioxin levels were similar to those of 404 other enlisted Ranch Hand veterans who had a single dioxin measurement made in 1987. The average time between the measurements was 0.61 years, the first measurement made from blood drawn on 10 April 1987 and the second from blood collected at a subsequent physical examination. In original unit, the coefficient of reliability was 0.87 (95% confidence interval: 0.76, 0.94) when the first measurement was at or below 50 parts per trillion. The measurement had no reliability in original units when the first measurement was greater than 50 parts per trillion. After a logarithmic transformation, the coefficient of reliability was 0.96 (95% confidence interval: 0.93 to 0.98). These results suggest that the serum dioxin measurement should not be used in original units for any purpose when the value exceeds 50 parts per trillion. The measurement is, however, highly reliable after a logarithmic transformation over the entire range of concentrations. Other studies using the same analytical method to measure dioxin in serum could similarly benefit if the measurement used is on the natural logarithm scale.

Exposure of the US population to environmental tobacco smoke: the Third National Health and Nutrition Examination Survey, 1988 to 1991.

OBJECTIVE: To estimate the extent of exposure of the US population to environmental tobacco smoke and the contribution of the home and workplace environment to environmental tobacco smoke exposure. DESIGN: Nationally representative cross-sectional survey including questionnaire information from persons aged 2 months and older (n=16818) and measurements of serum cotinine (a metabolite of nicotine) from persons aged 4 years and older (n=10642). SETTING/PARTICIPANTS: Participants in the Third National Health and Nutrition Examination Survey, October 25, 1988, to October 21, 1991. RESULTS: Of US children aged 2 months to 11 years, 43% lived in a home with at least 1 smoker, and 37% of adult non-tobacco users lived in a home with at least 1 smoker or reported environmental tobacco smoke exposure at work. Serum cotinine levels indicated more widespread exposure to nictoine. Of non-tobacco users, 87.9% had detectable levels of serum cotinine. Both the number of smokers in the household and the hours exposed at work were significantly and independently associated (P<.001, multiple regression t test) with increased serum cotinine levels. Serum cotinine levels of children, non-Hispanic blacks, and males indicated that these groups had higher exposure to environmental tobacco smoke. Dietary variables showed no consistent association with serum cotinine levels, and dietary contribution to serum cotinine level, if any, appeared to be extremely small. CONCLUSIONS: The high proportion of the population with detectable serum cotinine levels indicates widespread exposure to environmental tobacco smoke in the US population. Both the home and workplace environments significantly contribute to environmental tobacco smoke exposure in the United States.

Pharmacokinetics of TCDD in veterans of Operation Ranch Hand: 10-year follow-up.

Using multiple measurements from serum collected over 10 yr (1982, 1987, and 1992), we estimated the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in 213 veterans of Operation Ranch Hand, the Air Force unit responsible for the aerial spraying of Agent Orange in Vietnam. The potential influences of age, percent body fat, and changes in percent body fat on the half-life estimate were also examined. The mean decay rate of TCDD for these veterans is 0.0797 per year with 95% confidence interval 0.0727 to 0.0868 per year; the corresponding half-life estimate is 8.7 yr with 95% confidence interval 8.0-9.5 yr. Half-life increased significantly with increasing body fat, but not with age or relative changes in percent body fat.

p-Dichlorobenzene exposure among 1,000 adults in the United States.

p-Dichlorobenzene is used widely in the United States as a room deodorizer, a moth repellent, and a precursor for a polymer. In a previous study of selected children in Arkansas, we found that 96% of the children had detectable urinary concentrations of 2,5-dichlorophenol, the metabolite of p-dichlorobenzene. In the current study, we found that, in a sample of 1,000 adults who lived throughout the United States, 98% had detectable levels of 2,5-dichlorophenol in their urine, and 96% had detectable levels of p-dichlorobenzene in their blood. Urinary 2,5-dichlorophenol concentrations ranged up to 8,700 micrograms/l (median and mean concentrations of 30 micrograms/l and 200 micrograms/l, respectively). p-Dichlorobenzene blood concentrations ranged up to 49 micrograms/l, with median and mean concentrations of 0.33 micrograms/l and 2.1 micrograms/l, respectively. The Pearson correlation coefficient for 2,5-dichlorophenol in urine and p-dichlorobenzene in blood was .82 (p < .0001), thus demonstrating a strong association between these exposure measurements. Neither age nor gender was related to urinary 2,5-dichlorophenol or blood p-dichlorobenzene concentrations (p > .40). When these results are viewed with data from other studies, the collective data show that p-dichlorobenzene is a common, worldwide contaminant. The high prevalence of exposure to p-dichlorobenzene, coupled with its potential for adverse health effects, indicate the need for more detailed studies, including studies of long-term health effects on exposed populations.

Improving exposure assessment by monitoring human tissues for toxic chemicals.

Typically, the availability of appropriate data to estimate human exposures to toxic chemicals is scarce. Consequently, exposure assessments are often based on indirect surrogates of exposure, such as a combination of questionnaire data on time-activities and concentrations of toxic chemicals measured in environmental media (e.g., air, water, food, soil, dust). Recent advances, however, make it technically feasible and relatively affordable to measure low levels of multiple toxic chemicals in accessible human tissues (e.g., blood, urine). The increasing availability of biological markers for exposure, along with improvements in pharmacokinetic understanding, present new opportunities to estimate exposure from human tissue measurements and from knowledge of intake and uptake parameters. Biological monitoring provides exposure information that is usually complementary to the type of exposure information obtained from environmental monitoring. Biological and environmental monitoring can be used separately or together in order to meet desired objectives. We present here a discussion of the value of biological monitoring for improving exposure assessment. We emphasize the role of biological monitoring in identifying high-priority exposures, evaluating the effectiveness of intervention and prevention efforts, identifying at-risk subpopulations, recognizing time trends in population exposures, establishing reference ranges of tissue concentrations, and providing integrated dose measurements.