Carolyn M. Gallagher

Urinary Cadmium and Osteoporosis in U.S. Women ≥50 Years of Age: NHANES 1988–1994 and 1999–2004

Background Urinary cadmium (U-Cd) has been associated with decreased peripheral bone mineral density (BMD) and osteoporosis. This association, however, has not been confirmed using femoral BMD, the international standard for diagnosing osteoporosis, at levels < 1.0 μg Cd/g creatinine. Objectives Our goal was to investigate the statistical association between U-Cd, at levels ≤ 1 μg/g creatinine, and osteoporosis, as indicated by hip BMD and self-report in a population-based sample of U.S. women ≥ 50 years of age. Methods We drew data from the National Health and Nutrition Examination Surveys for 1988–1994 (n = 3,207) and 1999–2004 (n = 1,051). Osteoporosis was indicated by hip BMD cutoffs based on the international standard and self-report of physician diagnosis. We analyzed U-Cd levels for association with osteoporosis using multiple logistic regression. Results Women ≥ 50 years of age with U-Cd levels between 0.50 and 1.00 μg/g creatinine were at 43% greater risk for hip-BMD–defined osteoporosis, relative to those with levels ≤ 0.50 μg/g (odds ratio = 1.43; 95% confidence interval, 1.02–2.00; p = 0.04). We observed similar effect estimates using self-report of physician-diagnosed osteoporosis. Smokers did not show a statistically increased risk. Conclusions Results suggest that U.S. women are at risk for osteoporosis at U-Cd levels below the U.S. Occupational Safety and Health Administration’s 3-μg/g safety standard. Given null findings among smokers, dietary Cd, rather than tobacco, is the likely source of Cd-related osteoporosis risk for the U.S. female population ≥ 50 years of age.

Blood and Urine Cadmium, Blood Pressure, and Hypertension: A Systematic Review and Meta-analysis

Background Cadmium exposure has been inconsistently related to blood pressure. Objectives We updated and reevaluated the evidence regarding the relationships of blood cadmium (BCd) and urine cadmium (UCd) with blood pressure (BP) and hypertension (HTN) in nonoccupationally exposed populations. Data sources and extraction We searched PubMed and Web of Science for articles on BCd or UCd and BP or HTN in nonoccupationally exposed populations and extracted information from studies that provided sufficient data on population, smoking status, exposure, outcomes, and design. Data synthesis Twelve articles met inclusion criteria: eight provided data adequate for comparison, and five reported enough data for meta-analysis. Individual studies reported significant positive associations between BCd and systolic BP (SBP) among nonsmoking women [β = 3.14 mmHg per 1 μg/L untransformed BCd; 95% confidence interval (CI), 0.14–6.14] and among premenopausal women (β = 4.83 mmHg per 1 nmol/L log-transformed BCd; 95% CI, 0.17–9.49), and between BCd and diastolic BP (DBP) among women (β = 1.78 mmHg comparing BCd in the 90th and 10th percentiles; 95% CI, 0.64–2.92) and among premenopausal women (β = 3.84 mmHg per 1 nmol/L log-transformed BCd; 95% CI, 0.86–6.82). Three meta-analyses, each of three studies, showed positive associations between BCd and SBP (p = 0.006) and DBP (p < 0.001) among women, with minimal heterogeneity (I2 = 3%), and a significant inverse association between UCd and HTN among men and women, with substantial heterogeneity (I2 = 80%). Conclusion Our results suggest a positive association between BCd and BP among women; the results, however, are inconclusive because of the limited number of representative population-based studies of never-smokers. Associations between UCd and HTN suggest inverse relationships, but inconsistent outcome definitions limit interpretation. We believe a longitudinal study is merited.

Hepatitis B vaccination of male neonates and autism diagnosis, NHIS 1997-2002.

Universal hepatitis B vaccination was recommended for U.S. newborns in 1991; however, safety findings are mixed. The association between hepatitis B vaccination of male neonates and parental report of autism diagnosis was determined. This cross-sectional study used weighted probability samples obtained from National Health Interview Survey 1997–2002 data sets. Vaccination status was determined from the vaccination record. Logistic regression was used to estimate the odds for autism diagnosis associated with neonatal hepatitis B vaccination among boys age 3–17 years, born before 1999, adjusted for race, maternal education, and two-parent household. Boys vaccinated as neonates had threefold greater odds for autism diagnosis compared to boys never vaccinated or vaccinated after the first month of life. Non-Hispanic white boys were 64% less likely to have autism diagnosis relative to nonwhite boys. Findings suggest that U.S. male neonates vaccinated with the hepatitis B vaccine prior to 1999 (from vaccination record) had a threefold higher risk for parental report of autism diagnosis compared to boys not vaccinated as neonates during that same time period. Nonwhite boys bore a greater risk.

The relationship between body iron stores and blood and urine cadmium concentrations in US never-smoking, non-pregnant women aged 20–49 years

BACKGROUND Cadmium is a ubiquitous environmental pollutant associated with increased risk of leading causes of mortality and morbidity in women, including breast cancer and osteoporosis. Iron deficiency increases absorption of dietary cadmium, rendering women, who tend to have lower iron stores than men, more susceptible to cadmium uptake. We used body iron, a measure that incorporates both serum ferritin and soluble transferrin receptor, as recommended by the World Health Organization, to evaluate the relationships between iron status and urine and blood cadmium. METHODS Serum ferritin, soluble transferrin receptor, urine and blood cadmium values in never-smoking, non-pregnant, non-lactating, non-menopausal women aged 20-49 years (n=599) were obtained from the 2003-2008 National Health and Nutrition Examination Surveys. Body iron was calculated from serum ferritin and soluble transferrin receptor, and iron deficiency defined as body iron <0 mg/kg. Robust linear regression was used to evaluate the relationships between body iron and blood and urine cadmium, adjusted for age, race, poverty, body mass index, and parity. RESULTS Per incremental (mg/kg) increase in body iron, urine cadmium decreased by 0.003 μg/g creatinine and blood cadmium decreased by 0.014 μg/L. Iron deficiency was associated with 0.044 μg/g creatinine greater urine cadmium (95% CI=0.020, 0.069) and 0.162 μg/L greater blood cadmium (95% CI=0.132, 0.193). CONCLUSIONS Iron deficiency is a risk factor for increased blood and urine cadmium among never-smoking, pre-menopausal, non-pregnant US women, independent of age, race, poverty, body mass index and parity. Expanding programs to detect and correct iron deficiency among non-pregnant women merits consideration as a potential means to reduce the risk of cadmium associated diseases.

Hepatitis B triple series vaccine and developmental disability in US children aged 1–9 years

This study investigated the association between vaccination with the Hepatitis B triple series vaccine prior to 2000 and developmental disability in children aged 1–9 years (n = 1824), proxied by parental report that their child receives early intervention or special education services (EIS). National Health and Nutrition Examination Survey 1999–2000 data were analyzed and adjusted for survey design by Taylor Linearization using SAS version 9.1 software, with SAS callable SUDAAN version 9.0.1. The odds of receiving EIS were approximately nine times as great for vaccinated boys (n = 46) as for unvaccinated boys (n = 7), after adjustment for confounders. This study found statistically significant evidence to suggest that boys in United States who were vaccinated with the triple series Hepatitis B vaccine, during the time period in which vaccines were manufactured with thimerosal, were more susceptible to developmental disability than were unvaccinated boys.

Cadmium, follicle-stimulating hormone, and effects on bone in women age 42-60 years, NHANES III.

BACKGROUND Increased body burden of environmental cadmium has been associated with greater risk of decreased bone mineral density (BMD) and osteoporosis in middle-aged and older women, and an inverse relationship has been reported between follicle-stimulating hormone (FSH) and BMD in middle-aged women; however, the relationships between cadmium and FSH are uncertain, and the associations of each with bone loss have not been analyzed in a single population. OBJECTIVES The objective of this study was to evaluate the associations between creatinine-adjusted urinary cadmium (UCd) and FSH levels, and the associations between UCd and FSH with BMD and osteoporosis, in postmenopausal and perimenopausal women aged 42-60 years. METHODS Data were obtained from the Third National Health Examination and Nutrition Survey, 1988-1994 (NHANES III). Outcomes evaluated were serum FSH levels, femoral bone mineral density measured by dual energy X-ray absorptiometry, and osteoporosis indicated by femoral BMD cutoffs based on the international standard. Urinary cadmium levels were analyzed for association with these outcomes, and FSH levels analyzed for association with bone effects, using multiple regression. Subset analysis was conducted by a dichotomous measure of body mass index (BMI) to proxy higher and lower adipose-synthesized estrogen effects. RESULTS UCd was associated with increased serum FSH in perimenopausal women with high BMI (n=642; beta=0.45; p< or =0.05; R(2)=0.35) and low BMI (n=408; beta=0.61; p< or =0.01; R(2)=0.34). Among perimenopausal women with high BMI, BMD was inversely related to UCd (beta=-0.04; p< or =0.05) and FSH (beta=-0.03; p< or =0.05). In postmenopausal women with low BMI, an incremental increase in FSH was associated with 2.78 greater odds for osteoporosis (109 with and 706 without) (OR=2.78; 95% CI=1.43, 5.42; p< or =0.01). CONCLUSION Long-term cadmium exposure at environmental levels is associated with increased serum FSH, and both FSH and UCd are associated with bone loss, in US women aged 42-60 years.

Total blood mercury, plasma homocysteine, methylmalonic acid and folate in US children aged 3-5 years, NHANES 1999-2004

BACKGROUND Mercury is a known neurotoxicant; however, the relationship between childhood exposures and neurodevelopmental outcomes is uncertain, and may be modified by nutrition-related susceptibilities. In vitro studies found that mercury inhibited methionine synthase, an enzyme that interacts with vitamin B-12 and folate to regenerate the amino acid methionine from homocysteine, and inhibition of methionine synthase diverted homocysteine to cysteine and glutathione synthesis. The relationships between mercury, homocysteine, B-12, and folate have not been examined in children. OBJECTIVE This study aimed to evaluate associations between Hg and homocysteine in male and female children differentiated by higher and lower methylmalonic acid (MMA, an indicator of vitamin B-12 deficiency) and folate status. DESIGN Cross-sectional data on total blood mercury (Hg), plasma homocysteine, MMA, and serum folate were obtained from the 1999-2004 National Health and Nutrition Examination Surveys for children aged 3-5 years (n=1005). We used multiple linear regression to evaluate relationships between homocysteine and Hg quartiles, stratified by sex, MMA ≥ and folate < sample medians, adjusted for demographic, anthropometric, and environmental factors. RESULTS In boys with higher MMA and lower folate (n=135), but not in other children, we observed inverse associations between homocysteine and Hg. Children with Hg >3.49 μmol/L showed 1.14 μmol/L lower homocysteine (p<0.001) relative to the lowest quartile (≤ 0.70 μmol/L) {p-value for trend<0.001}. Compared to other subsamples, this subsample had significantly higher homocysteine levels. CONCLUSION Hg was inversely correlated with plasma homocysteine in young boys, but not girls, with higher MMA and lower folate. Additional studies are merited to evaluate Hg and amino acid metabolism in susceptible children.

Mercury and thyroid autoantibodies in U.S. women, NHANES 2007–2008

Associations between positive thyroid autoantibodies and total blood mercury in women were evaluated using the National Health and Nutrition Examination Survey (NHANES), 2007-2008. Women are at increased risk for autoimmune disorders, mercury exposure has been associated with cellular autoimmunity and mercury accumulates in the thyroid gland. We used multiple logistic regression to evaluate the associations between total bloodmercury and thyroglobulin autoantibody antibody positivity and thyroid peroxidase autoantibody positivity in non-pregnant, non-lactating women aged 20 and older not currently using birth control pills or other hormone therapies, adjusted for demographic factors, menopausal status, nutrient intake and urine iodine (n=2047). Relative to women with the lowest mercury levels (≤0.40 μg/L), women with mercury >1.81 μg/L (upper quintile) showed 2.24 (95% CI=1.22, 4.12) greater odds for thyroglobulin autoantibody positivity (p(trend)=0.032); this relationship was not evident for thyroid peroxidase autoantibody positivity. Results suggest an association between mercury and thyroglobulin autoantibody positivity.

Total blood mercury and rubella antibody concentrations in US children aged 6–11 years, NHANES 2003–2004

BACKGROUND Children are susceptible to mercury toxicity, and mercury has immunomodulatory effects. Lower folate and B-12, and higher homocysteine may represent susceptibility cofactors. A large proportion of variability in rubella immune response is attributable to environmental factors. OBJECTIVE This study aimed to evaluate the interaction between total blood mercury (Hg) and nutritional and homocysteine status on rubella virus antibody concentrations. DESIGN Cross-sectional data on rubella IgG antibody concentrations, Hg, homocysteine, methylmalonic acid (MMA, an indicator of B-12 deficiency), and folate were obtained from 2003-2004 NHANES for children aged 6-11 years with rubella seropositivity (n=690). Linear regression was used to evaluate relationships between log-transformed rubella concentrations and Hg, stratified by sex, MMA ≥, folate<, and homocysteine ≥ sample medians, adjusted for demographic and nutritional cofactors. RESULTS Hg was significantly positively associated with rubella antibody concentrations (β=0.24; 95% confidence interval (CI)=0.11, 0.38) in children with higher MMA, lower folate and higher homocysteine (n=110), yet inversely associated among all other children (β=-0.18; 95% CI=-0.34, -0.03) (n=580). Among the former, estimates (β) were positive across all Hg quartiles relative to the lowest (Q1) (Hg<0.30 μg/L): Q2: β=0.23 (-.10, 0.56); Q3: β=0.35 (0.13, 0.57); Q4: β=0.53 (0.21, 0.84); P(trend)<0.01. CONCLUSION Findings are consistent with previously reported associations between Hg and measles antibody concentrations, and highlight the importance of considering dynamics between toxicant exposures, pathogens and host susceptibility.

Total blood mercury and serum measles antibodies in US children, NHANES 2003–2004

BACKGROUND Environmental toxins, pathogens and host susceptibility cofactors may interact to contribute to disease. In vitro mercury exposure inhibited antiviral cytokines in human cells; however, little is known about the relationship between mercury and viruses in children. Children are susceptible to mercury toxicity; lower vitamin B-12 and folate levels and higher homocysteine levels may represent susceptibility cofactors. This study aimed to evaluate associations between total blood mercury (Hg) and measles antibodies in children, and the influence of these susceptibility cofactors. DESIGN Cross-sectional data on serum measles antibodies, Hg, homocysteine, methylmalonic acid (MMA, indicator of B-12 deficiency), and folate were obtained from the 2003-2004 NHANES for children aged 6-11 years with measles seropositivity (n=692). We used linear regression to evaluate relationships between measles antibodies and Hg, stratified by sex, MMA ≥, folate <, and homocysteine≥sample medians, adjusted for demographic, nutritional and environmental cofactors. RESULTS Hg (range: 0.10-19.10μg/L) was inversely associated with measles antibodies (range: 1.00-28.24 units) in non-stratified analysis (n=692), yet positively associated among the subset of boys with higher MMA and lower folate (n=98). Among this subset with higher homocysteine levels (n=61), correlations were positive across all Hg quartiles relative to Q1 (Hg≤0.20μg/L): Q2:β=6.60 (3.02, 10.19); Q3:β=8.49 (6.17, 10.81); Q4 (Hg>0.80μg/L):β=4.90 (2.12, 7.67) (p(trend)=0.077). CONCLUSION Stratification by susceptibility cofactors revealed opposing directionality for correlations between Hg and measles antibodies, with positive effect estimates at lowest exposures only among boys with higher MMA, lower folate and higher homocysteine levels.