James L. Pirkle

Urinary Creatinine Concentrations in the U.S. Population: Implications for Urinary Biologic Monitoring Measurements

Biologic monitoring (i.e., biomonitoring) is used to assess human exposures to environmental and workplace chemicals. Urinary biomonitoring data typically are adjusted to a constant creatinine concentration to correct for variable dilutions among spot samples. Traditionally, this approach has been used in population groups without much diversity. The inclusion of multiple demographic groups in studies using biomonitoring for exposure assessment has increased the variability in the urinary creatinine levels in these study populations. Our objectives were to document the normal range of urinary creatinine concentrations among various demographic groups, evaluate the impact that variations in creatinine concentrations can have on classifying exposure status of individuals in epidemiologic studies, and recommend an approach using multiple regression to adjust for variations in creatinine in multivariate analyses. We performed a weighted multivariate analysis of urinary creatinine concentrations in 22,245 participants of the Third National Health and Nutrition Examination Survey (1988–1994) and established reference ranges (10th–90th percentiles) for each demographic and age category. Significant predictors of urinary creatinine concentration included age group, sex, race/ethnicity, body mass index, and fat-free mass. Time of day that urine samples were collected made a small but statistically significant difference in creatinine concentrations. For an individual, the creatinine-adjusted concentration of an analyte should be compared with a “reference” range derived from persons in a similar demographic group (e.g., children with children, adults with adults). For multiple regression analysis of population groups, we recommend that the analyte concentration (unadjusted for creatinine) should be included in the analysis with urinary creatinine added as a separate independent variable. This approach allows the urinary analyte concentration to be appropriately adjusted for urinary creatinine and the statistical significance of other variables in the model to be independent of effects of creatinine concentration.

Trends in the Exposure of Nonsmokers in the U.S. Population to Secondhand Smoke: 1988–2002

The objective of this study was to describe the exposure of nonsmokers in the U.S. population to secondhand smoke (SHS) using serum cotinine concentrations measured over a period of 14 years, from October 1988 through December 2002. This study consists of a series of National Health and Nutrition Examination Surveys (NHANES) measuring serum cotinine as an index of SHS exposure of participants. Study participants were individuals representative of the U.S. civilian, noninstitutionalized population, ≥ 4 years of age. We analyzed serum cotinine and interview data from NHANES obtained during surveys conducted during four distinct time periods. Our results document a substantial decline of approximately 70% in serum cotinine concentrations in non-smokers during this period. This decrease was reflected in all groups within the population regardless of age, sex, or race/ethnicity. The large decrease that we observed in serum cotinine concentrations suggests a substantial reduction in the exposure of the U.S. population to SHS during the 1990s. The exposure of nonsmokers to SHS represents an important public health concern. Our findings suggest that recent public health efforts to reduce such exposures have had an important effect, although children and non-Hispanic black nonsmokers show relatively higher levels of serum cotinine.

Trends in Blood Lead Levels and Blood Lead Testing Among US Children Aged 1 to 5 Years, 1988–2004

OBJECTIVES. To evaluate trends in childrens blood lead levels and the extent of blood lead testing of children at risk for lead poisoning from national surveys conducted during a 16-year period in the United States. METHODS. Data for children aged 1 to 5 years from the National Health and Nutrition Examination Survey III Phase I, 1988–1991, and Phase II, 1991–1994 were compared to data from the survey period 1999–2004. RESULTS. The prevalence of elevated blood lead levels, ≥10 μg/dL, among children decreased from 8.6% in 1988–1991 to 1.4% in 1999–2004, which is an 84% decline. From 1988–1991 and 1999–2004, childrens geometric mean blood lead levels declined in non-Hispanic black (5.2–2.8 μg/dL), Mexican American (3.9–1.9 μg/dL), and non-Hispanic white children (3.1 μg/dL to 1.7 μg/dL). However, levels continue to be highest among non-Hispanic black children relative to Mexican American and non-Hispanic white children. Blood lead levels were distributed as follows: 14.0% were <1.0 μg/dL, 55.0% were 1.0 to <2.5 μg/dL, 23.6% were 2.5 to <5 μg/dL, 4.5% were 5 to <7.5 μg/dL, 1.5% were 7.5 to <10 μg/dL, and 1.4% were ≥10 μg/dL. Multivariable analysis indicated that residence in older housing, poverty, age, and being non-Hispanic black are still major risk factors for higher lead levels. Blood lead testing of Medicaid-enrolled children increased to 41.9% from 19.2% in 1988–1991. Only 43.0% of children with elevated blood lead levels had previously been tested. CONCLUSIONS. Childrens blood lead levels continue to decline in the United States, even in historically high-risk groups for lead poisoning. To maintain progress made and eliminate remaining disparities, efforts must continue to test children at high risk for lead poisoning, and identify and control sources of lead. Coordinated prevention strategies at national, state, and local levels will help achieve the goal of elimination of elevated blood lead levels.

Urinary perchlorate and thyroid hormone levels in adolescent and adult men and women living in the United States.

Background Perchlorate is commonly found in the environment and known to inhibit thyroid function at high doses. Assessing the potential effect of low-level exposure to perchlorate on thyroid function is an area of ongoing research. Objectives We evaluated the potential relationship between urinary levels of perchlorate and serum levels of thyroid stimulating hormone (TSH) and total thyroxine (T4) in 2,299 men and women, ≥ 12 years of age, participating in the National Health and Nutrition Examination Survey (NHANES) during 2001–2002. Methods We used multiple regression models of T4 and TSH that included perchlorate and covariates known to be or likely to be associated with T4 or TSH levels: age, race/ethnicity, body mass index, estrogen use, menopausal status, pregnancy status, premenarche status, serum C-reactive protein, serum albumin, serum cotinine, hours of fasting, urinary thiocyanate, urinary nitrate, and selected medication groups. Results Perchlorate was not a significant predictor of T4 or TSH levels in men. For women overall, perchlorate was a significant predictor of both T4 and TSH. For women with urinary iodine < 100 μg/L, perchlorate was a significant negative predictor of T4 (p < 0.0001) and a positive predictor of TSH (p = 0.001). For women with urinary iodine ≥ 100 μg/L, perchlorate was a significant positive predictor of TSH (p = 0.025) but not T4 (p = 0.550). Conclusions These associations of perchlorate with T4 and TSH are coherent in direction and independent of other variables known to affect thyroid function, but are present at perchlorate exposure levels that were unanticipated based on previous studies.

Estimates of the half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin in Vietnam veterans of Operation Ranch Hand

The half-life of 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD; commonly known as dioxin) in serum has been measured in 36 Air Force Vietnam veterans of Operation Ranch Hand, which was the operation that aerially sprayed the herbicide Agent Orange in Vietnam. From serum specimens taken in 1982 and 1987, the median half-life of 2,3,7,8-TCDD in these Ranch Hand veterans was found to be 7.1 yr (95% confidence interval about the median of 5.8-9.6 yr). These veterans reported no civilian exposure to dioxin or herbicides. Concentrations of 2,3,7,8-TCDD in the 1982 serum specimens from these veterans ranged from 16.9 to 423 parts per trillion on a lipid weight basis. The half-life estimates were not associated with the concentration of 2,3,7,8-TCDD in the 1982 serum specimens. This half-life of 7.1 yr is much longer than the half-life of 2,3,7,8-TCDD reported in animals but is consistent with recent evidence from other human exposures to 2,3,7,8-TCDD.

Environmental tobacco smoke and pregnancy outcome.

Background: Recent reviews conclude that environmental tobacco smoke (ETS) leads to diminished birth weight. However, the threshold and magnitude of that effect is uncertain. We aimed to determine the magnitude and shape of the relations between ETS and various adverse pregnancy outcomes using a highly sensitive biochemical assay. Methods: Maternal serum specimens were collected from more than 3000 women enrolled in Californias prenatal screening program in 1992 and analyzed for cotinine. Information on pregnancy outcomes was obtained from live birth/fetal death records and hospital questionnaires. We conducted analyses on 2777 woman–live birth pairs and 19 woman–fetal death pairs in which the mother was presumed to be a nonsmoker (midtrimester cotinine levels ≤10 ng/mL). Results: In multiple logistic regression analyses, the odds ratios of fetal death, preterm delivery, and term-low birth weight were 3.4, 1.8, and 1.8, respectively, in the highest cotinine quintile (0.236–10 ng/mL), compared with the lowest quintile (<0.026 ng/mL). In adjusted linear models, there was a linear dose-dependent effect of log cotinine on mean birth weight (−109 g) and mean infant length (−0.84 cm) over the range of cotinine values. Linear relations were not found with respect to infant head circumference or the ratio of brain weight to body weight. Infants body mass index declined with exposures above approximately 0.5 ng/mL cotinine. We estimated that ETS levels at or above 0.05 ng/mL (experienced by 62% of the study population) accounted for 12% of all adverse outcomes. Conclusions: ETS exposure in pregnant women adversely affects pregnancy by increasing fetal mortality and preterm delivery at higher exposure levels and slowing fetal growth across all levels of ETS exposure.

Perchlorate Exposure of the US Population, 2001-2002

Perchlorate is commonly found in the environment and can impair thyroid function at pharmacological doses. As a result of the potential for widespread human exposure to this biologically active chemical, we assessed perchlorate exposure in a nationally representative population of 2820 US residents, ages 6 years and older, during 2001 and 2002 as part of the National Health and Nutrition Examination Survey (NHANES). We found detectable levels of perchlorate (>0.05 μg/l) in all 2820 urine samples tested, indicating widespread human exposure to perchlorate. Urinary perchlorate levels were distributed in a log normal fashion with a median of 3.6 μg/l (3.38 μg/g creatinine) and a 95th percentile of 14 μg/l (12.7 μg/g creatinine). When geometric means of urinary perchlorate levels were adjusted for age, fasting, sex and race-ethnicity, we found significantly higher levels of urinary perchlorate in children compared with adolescents and adults. We estimated total daily perchlorate dose for each adult (ages 20 years and older), based on urinary perchlorate, urinary creatinine concentration and physiological parameters predictive of creatinine excretion rate. The 95th percentile of the distribution of estimated daily perchlorate doses in the adult population was 0.234 μg/kg-day [CI 0.202–0.268 μg/kg-day] and is below the EPA reference dose (0.7 μg/kg-day), a dose estimated to be without appreciable risk of adverse effects during a lifetime of exposure. These data provide the first population-based assessment of the magnitude and prevalence of perchlorate exposure in the US.

Human Biomonitoring of Environmental Chemicals

be controlled most rigorously? One strategy is to go after the largest sources of pollution. This approach cer tainly makes sense when those pollu tants have obvious and widespread consequences, such as warming the globe, causing algal blooms, eroding the ozone layer or killing off wildlife. But for protecting human health, this strate gy does not serve so well, because the link between a given compound and its biological effects can be difficult to gauge. For epidemiologists to correlate environmental pollutants with health problems, they need to know who has been exposed and at what level. This knowledge is exceptionally dif ficult to gain when there is a lag be tween exposure and the manifestation of illness. In such cases, the data are seldom?if ever?sufficient to deter

A Case of Naturally Acquired Inhalation Anthrax: Clinical Care and Analyses of Anti-Protective Antigen Immunoglobulin G and Lethal Factor

This report describes the first case of naturally acquired inhalation anthrax in the United States since 1976. The patients clinical course included adjunctive treatment with human anthrax immunoglobulin. Clinical correlation of serologic assays for the lethal factor component of lethal toxin and anti-protective antigen immunoglobulin G are also presented.

Exposure of casino employees to environmental tobacco smoke.

Environmental and medical evaluations were performed to evaluate occupational exposure to environmental tobacco smoke (ETS) among casino employees. Air concentrations of both nicotine and respirable dust were similar to those published in the literature for other non-industrial indoor environments. The geometric mean serum cotinine level of the 27 participants who provided serum samples was 1.34 nanograms per milliliter (ng/mL) (pre-shift) and 1.85 ng/mL (post-shift). Both measurements greatly exceeded the geometric mean value of 0.65 ng/mL for participants in the Third National Health and Nutrition Examination Survey (NHANES III) who reported exposure to ETS at work. This evaluation demonstrates that a sample of employees working in a casino gaming area were exposed to ETS at levels greater than those observed in a representative sample of the US population, and that the serum and urine cotinine of these employees increased during the workshift.