Role of renal function in the association of drinking water fluoride and plasma fluoride among adolescents in the United States: NHANES, 2013-2016.

CONTEXT: While fluoride has been added to drinking water and dental products for decades in order to prevent tooth decay, there are growing concerns about its potential toxicity. Given that fluoride is primarily excreted in urine, an important question that has not been examined is whether among those whose drinking water is fluoridated, impaired renal function is associated with higher levels of circulating fluoride. OBJECTIVE: To examine the association between drinking water and plasma fluoride and its modification by renal function. DESIGN, SETTING, AND PARTICIPANTS: Participants in the National Health and Nutrition Examination Survey (NHANES) between 2013 and 2016 with measures of fluoride in plasma and drinking water and renal function. These measures were only available in adolescent age 12-19 years. OUTCOMES: Plasma fluoride levels and their modification by strata of renal function, measured by the estimated glomerular filtration rate (eGFR). RESULTS: Among 1841 healthy adolescents, a 10 ml/min/1.73 m (Penman et al., 1997) lower eGFR and a 1 mg/L higher drinking water fluoride concentration were associated with a 0.02 (95%CI -0.02, -0.03) umol/L and 0.23 (95%CI 0.15,0.30) umol/L higher adjusted plasma fluoride level, respectively. The association of water and plasma fluoride levels was most robust among those with lower renal function (multiplicative interaction p value < 0.001). For adolescents in the lowest eGFR quartile, a 1 mg/L higher drinking water fluoride concentration was associated with a 0.35 (95%CI 0.21,0.48) umol/L higher plasma fluoride level, compared to 0.20 (95%CI 0.14,0.26) umol/L in the highest eGFR quartile. Restriction to those with measurable plasma fluoride levels yielded similar results. CONCLUSIONS: Water fluoridation results in higher plasma fluoride levels in those with lower renal function. How routine water fluoridation may affect the many millions of Americans with Chronic Kidney Disease, who are particularly susceptible to heavy metal and mineral accumulation, needs to be further investigated.

Association of Dietary Fluoride Intake and Diet Variables with Dental Caries in Adolescents from the ELEMENT Cohort Study.

To examine the association of dietary fluoride intake, total carbohydrate consumption and other key dietary variables with dental caries experience among adolescents, a cross-sectional analysis was conducted in a sample of 402 participants from the Early Life Exposures in Mexico to Environmental Toxicants cohort. The presence and severity of dental caries were assessed using the International Caries Detection and Assessment System (ICDAS) to calculate the number of decayed, missing, and filled teeth or surfaces (D1MFT/D4MFT). The dietary intake of fluoride, energy, carbohydrates, and food groups was estimated using a validated food frequency questionnaire (FFQ). Multivariate zero-inflated negative binomial regression models and negative binomial regression models were run to estimate the association of fluoride intake (mg/day) and total carbohydrate intake (g/day) with the D1MFT/D4MFT index. We found that 80% of the adolescents experienced dental caries (D1MFT >0), with 30% presenting cavitated lesions (D4MFT >0). The mean scores for D1MFT and D4MFT were 6.2 (SD 5.3) and 0.67 (SD 1.3), respectively. The median intake of fluoride estimated by the FFQ was 0.015 mg/kg/day. This intake was statistically higher in participants with a D4MFT = 0 compared to those with a D4MFT >0 (0.90 vs. 0.82 mg/day; 0.016 vs. 0.014 mg/kg/day; p < 0.05). For D1MFT, D1MFS, D4MFT, and D4MFS scores, a higher fluoride consumption (mg/day) from foods and beverages was associated with a statistically significant reduction in the number of lesions. The reported frequency of consumption of sugary foods in a whole day was statistically higher in those with D1MFT >0 than in those with D1MFT = 0 (p < 0.05). The total carbohydrate intake (g/day) was positively associated with dental caries experience. We conclude that a higher fluoride intake through foods and beverages is associated with a lower dental caries experience among adolescents; this effect was seen even when the dietary intake of fluoride was 0.015 mg/kg/day, which is lower than the average intake recommendation. In contrast, a higher total carbohydrate intake and the frequency of intake of sugary foods were associated with a higher dental caries experience, with no apparent threshold for the effects.

Uncovering neurodevelopmental windows of susceptibility to manganese exposure using dentine microspatial analyses.

BACKGROUND: Associations between manganese (Mn) and neurodevelopment may depend on dose and exposure timing, but most studies cannot measure exposure variability over time well. OBJECTIVE: We apply temporally informative tooth-matrix biomarkers to uncover windows of susceptibility in early life when Mn is associated with visual motor ability in childhood. We also explore effect modification by lead (Pb) and child sex. METHODS: Participants were drawn from the ELEMENT (Early Life Exposures in MExico and NeuroToxicology) longitudinal birth cohort studies. We reconstructed dose and timing of prenatal and early postnatal Mn and Pb exposures for 138 children by analyzing deciduous teeth using laser ablation-inductively coupled plasma-mass spectrometry. Neurodevelopment was assessed between 6 and 16 years of age using the Wide Range Assessment of Visual Motor Abilities (WRAVMA). Mn associations with total WRAVMA scores and subscales were estimated with multivariable generalized additive mixed models. We examined Mn interactions with Pb and child sex in stratified models. RESULTS: Levels of dentine Mn were highest in the second trimester and declined steeply over the prenatal period, with a slower rate of decline after birth. Mn was positively associated with visual spatial and total WRAVMA scores in the second trimester, among children with lower (< median) tooth Pb levels: one standard deviation (SD) increase in ln-transformed dentine Mn at 150 days before birth was associated with a 0.15 [95% CI: 0.04, 0.26] SD increase in total score. This positive association was not observed at high Pb levels. In contrast to the prenatal period, significant negative associations were found in the postnatal period from ~ 6 to 12 months of age, among boys only: one SD increase in ln-transformed dentine Mn was associated with a 0.11 [95% CI: - 0.001, - 0.22] to 0.16 [95% CI: - 0.04, - 0.28] SD decrease in visual spatial score. CONCLUSIONS: Using tooth-matrix biomarkers with fine scale temporal profiles of exposure, we found discrete developmental windows in which Mn was associated with visual-spatial abilities. Our results suggest that Mn associations are driven in large part by exposure timing, with beneficial effects found for prenatal levels and toxic effects found for postnatal levels.

Prenatal Maternal Occupational Exposure and Postnatal Child Exposure to Elemental Mercury.

OBJECTIVES: Young children are highly vulnerable to elemental mercury toxicity, and elementary mercury exposure in young children in China unfortunately occurs regularly because of the wide use of fluorescent lamps, glass thermometers, and other mercury-contained items. This study aimed to summarize such recent cases in a referral clinic and to make recommendations for postexposure treatment and prevention of future exposure. METHODS: Patients were evaluated between January 2007 and December 2009 in environmental health facilities throughout China and were referred to our clinic. A total of 6 children younger than 4 years with significant elemental mercury exposure were included in this case series analysis. The total mercury content in blood and hair (fetal hair if necessary) and average 24-hour urine mercury concentrations were analyzed. Meso-2,3-dimercaptosuccinic acid or surgery was prescribed for the patient if necessary. RESULTS: Young children were found to be exposed in 3 ways as follows: prenatal exposure through maternal occupational contact in compact fluorescent-lamp factories (2 cases), broken thermometers (3 cases), and other causes of accidental inhalation of mercury vapor during the embryonic and lactation periods (1 case). For 3 cases caused by broken thermometers, x-ray images helped to identify the position of mercury residues. Local excision was used to remove mercury from the floor of the mouth in 1 case. One child was prescribed oral meso-2,3-dimercaptosuccinic acid, and a good response was received. CONCLUSIONS: Substitution of mercury-in-glass thermometers and vigilance to prevent women of childbearing age from occupational mercury exposure were suggested. Treatment selection should vary according to patient situations.

Relationships between lead biomarkers and diurnal salivary cortisol indices in pregnant women from Mexico City: a cross-sectional study.

BACKGROUND: Lead (Pb) exposure during pregnancy may increase the risk of adverse maternal, infant, or childhood health outcomes by interfering with hypothalamic-pituitary-adrenal-axis function. We examined relationships between maternal blood or bone Pb concentrations and features of diurnal cortisol profiles in 936 pregnant women from Mexico City. METHODS: From 2007-11 we recruited women from hospitals/clinics affiliated with the Mexican Social Security System. Pb was measured in blood (BPb) during the second trimester and in mothers' tibia and patella 1-month postpartum. We characterized maternal HPA-axis function using 10 timed salivary cortisol measurements collected over 2-days (mean: 19.7, range: 14-35 weeks gestation). We used linear mixed models to examine the relationship between Pb biomarkers and cortisol area under the curve (AUC), awakening response (CAR), and diurnal slope. RESULTS: After adjustment for confounders, women in the highest quintile of BPb concentrations had a reduced CAR (Ratio: -13%; Confidence Interval [CI]: -24, 1, p-value for trend < 0.05) compared to women in the lowest quintile. Tibia/patella Pb concentrations were not associated with CAR, but diurnal cortisol slopes were suggestively flatter among women in the highest patella Pb quantile compared to women in the lowest quantile (Ratio: 14%; CI: -2, 33). BPb and bone Pb concentrations were not associated with cortisol AUC. CONCLUSIONS: Concurrent blood Pb levels were associated with cortisol awakening response in these pregnant women and this might explain adverse health outcomes associated with Pb. Further research is needed to confirm these results and determine if other environmental chemicals disrupt hypothalamic-pituitary-adrenal-axis function during pregnancy.

Early Lead Exposure Associated with Molar Hypomineralization.

Purpose: The purpose of this study was to determine the association between prenatal and early life exposure to lead and the presence of molar hypomineralization (MH) in a group of Mexican children. Methods: A subset of participants of the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENTS) cohort study was examined for the presence of molar hypomineralization using European Academy of Pedi- atric Dentistry (EAPD) criteria. Prenatal lead exposure was assessed by K-ray fluorescence measurements of patella and tibia lead and by maternal blood lead levels by trimester and averaged over trimesters. Postnatal exposure was assessed by levels of maternal blood lead at delivery and child blood lead at 12 and 24 months. Results: A subset of 506 subjects from the ELEMENT cohorts (nine to 18 years old) were examined for MH; 87 subjects (17.2 percent) had MH. Maternal blood lead levels in the third trimester (odds ratio [OR] equals 1.08; 95 percent confidence interval [95% CI] equals 1.02 to 1.15) and averaged over three trimesters (OR equals 1.10; 95% CI equals 1.02 to 1.19) were significantly associated with MH status. None of the maternal bone lead or the child's blood lead parameters was significantly associated with the presence of MH (P>0.05). Conclusions: This study documents a significant association between prenatal lead exposure especially in late pregnancy and the odds of molar hypomineralization.

Blood levels of lead and dental caries in permanent teeth.

OBJECTIVES: The purpose of this study was to determine whether there is an association between lead exposure within the ages of 1-4 years and dental caries in the permanent dentition between ages 9-17 among Mexican youth. METHODS: Data were collected for the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort from a group of 490 children born and reared in Mexico City. Among ages 1-4 years, blood lead levels were measured in micrograms of lead per deciliter of blood (µg/dL) and the presence of caries in adolescence was determined using the International Caries and Detection and Assessment System (ICDAS). The relationship between blood levels of lead and decayed, missing, or filled surfaces (DMFS) was examined using negative binomial regression. Covariates were selected based on previous studies and included age, gender, socioeconomic status, oral hygiene, body mass index, and diet. The nonlinear relationship between lead and DMFS was examined using smoothing splines. RESULTS: The mean overall blood lead level (BLL) was 4.83 µg/dL (S.D. of 2.2). The mean overall caries level (DMFS) was 4.1. No statistically significant association was found between early childhood blood lead levels and dental caries in adolescence. CONCLUSION: This study shows a lack of association between exposure to lead between the ages of 1-4 years of age and dental caries in permanent dentition later in life. Other covariates, such as age and sugar consumption, appeared to play a more prominent role in caries development.

The associations between lead exposure at multiple sensitive life periods and dental caries risks in permanent teeth.

BACKGROUND: Dental caries is an important public health problem in Mexico, a country also faced with high exposure to toxicants including lead (Pb). METHODS: Participants were 386 children living in Mexico City. Prenatal (trimester 1-3), early-childhood (12, 24, 36, and 48 months of age) and peri-pubertal (10-18 years of age) blood Pb levels were quantified using graphite-furnace atomic-absorption spectroscopy. Maternal patella and tibia bone Pb at 1 month postpartum were quantified with K X-ray fluorescence instrument. Dental caries presence was evaluated using decayed, missing, and filled teeth (DMFT) scores. Peri-pubertal sugar sweetened beverage (SSB) intake was estimated using a 116-item, interview-administered semi-quantitative food frequency questionnaire (FFQ). Total energy adjusted daily SSB intake was generated using the residual approach. Zero inflated negative binomial (ZINB) Poisson regression models were used to examine the associations between Pb with D1MFT and D4MFT at adolescence. RESULTS: Maternal second and third trimester and cumulative early childhood Pb exposure were positively associated with peri-pubertal D1MFT scores in unadjusted ZINB models (2nd trimester: RR = 1.17 (1.00, 1.37); 3rd trimester: RR = 1.20 (1.03, 1.40); early childhood: RR = 1.22 (1.02, 1.48)). These effect sizes were attenuated and no longer statistically significant after adjusting for covariates. When stratified by high/low SSB intake, a one unit increase of log-transformed 2nd trimester Pb exposure was associated with a 1.41 times (1.06, 1.86) higher D1MFT count, and 3rd trimester Pb exposure was associated with a 1.50 times (1.18, 1.90) higher D1MFT count among those with higher than median peri-pubertal SSB. Associations among those with lower SSB intake were roughly half those of the higher group and not statistically significant. CONCLUSIONS: Pb exposure during sensitive developmental periods was not statistically significantly associated with caries risk after accounting for confounders among our cohort. However, evidence from stratified analysis suggested a Pb-caries association among children with high SSB intake.

Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) Project.

PURPOSE: The Early Life Exposure in Mexico to ENvironmental Toxicants (ELEMENT) Project is a mother-child pregnancy and birth cohort originally initiated in the mid-1990s to explore: (1) whether enhanced mobilisation of lead from maternal bone stores during pregnancy poses a risk to fetal and subsequent offspring neurodevelopment; and (2) whether maternal calcium supplementation during pregnancy and lactation can suppress bone lead mobilisation and mitigate the adverse effects of lead exposure on offspring health and development. Through utilisation of carefully archived biospecimens to measure other prenatal exposures, banking of DNA and rigorous measurement of a diverse array of outcomes, ELEMENT has since evolved into a major resource for research on early life exposures and developmental outcomes. PARTICIPANTS: n=1643 mother-child pairs sequentially recruited (between 1994 and 2003) during pregnancy or at delivery from maternity hospitals in Mexico City, Mexico. FINDINGS TO DATE: Maternal bone (eg, patella, tibia) is an endogenous source for fetal lead exposure due to mobilisation of stored lead into circulation during pregnancy and lactation, leading to increased risk of miscarriage, low birth weight and smaller head circumference, and transfer of lead into breastmilk. Daily supplementation with 1200 mg of elemental calcium during pregnancy and lactation reduces lead resorption from maternal bone and thereby, levels of circulating lead. Beyond perinatal outcomes, early life exposure to lead is associated with neurocognitive deficits, behavioural disorders, higher blood pressure and lower weight in offspring during childhood. Some of these relationships were modified by dietary factors; genetic polymorphisms specific for iron, folate and lipid metabolism; and timing of exposure. Research has also expanded to include findings published on other toxicants such as those associated with personal care products and plastics (eg, phthalates, bisphenol A), other metals (eg, mercury, manganese, cadmium), pesticides (organophosphates) and fluoride; other biomarkers (eg, toxicant levels in plasma, hair and teeth); other outcomes (eg, sexual maturation, metabolic syndrome, dental caries); and identification of novel mechanisms via epigenetic and metabolomics profiling. FUTURE PLANS: As the ELEMENT mothers and children age, we plan to (1) continue studying the long-term consequences of toxicant exposure during the perinatal period on adolescent and young adult outcomes as well as outcomes related to the original ELEMENT mothers, such as their metabolic and bone health during perimenopause; and (2) follow the third generation of participants (children of the children) to study intergenerational effects of in utero exposures. TRIAL REGISTRATION NUMBER: NCT00558623.

Dentine biomarkers of prenatal and early childhood exposure to manganese, zinc and lead and childhood behavior.

BACKGROUND: Metal exposure alters neurodevelopmental outcomes; little is known about critical windows of susceptibility when exposure exerts the strongest effect. OBJECTIVE: To examine associations between dentine biomarkers of manganese (Mn), zinc (Zn) and lead (Pb) and later childhood behaviors. METHODS: Subjects enrolled in a longitudinal birth cohort study in Mexico City provided naturally shed deciduous teeth. We estimated weekly prenatal and postnatal dentine Mn, Zn and Pb concentrations in teeth using laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) and measured behavior at ages 8-11 years of age using the Behavior Assessment System for Children, 2nd edition (BASC-2). We used distributed lag models and lagged weighted quantile sum regression to identify the role of individual and combined dentine biomarkers of Mn, Zn and Pb on behavioral outcomes controlling for maternal education and gestational age. RESULTS: Among the 133 subjects included in this study, prenatal and early postnatal dentine Mn appeared protective against childhood behavioral problems, specifically hyperactivity and attention. Postnatal dentine Mn was associated with increased reporting of internalizing problems, specifically anxiety. At 6 months, a 1-unit increase (unit = 1 SD of log concentration) in Mn was associated with a 0.18-unit (unit = 1 SD of BASC-2 score) increase in internalizing symptoms score and a 0.25-unit increase in anxiety. Postnatal Pb was associated with increasing anxiety symptoms; at 12 months, a 1-unit increase in Pb was associated with a 0.4 unit increase in anxiety symptoms. When examined as a metal mixture, we observed two potential windows of susceptibility to increased anxiety symptoms: the first window (0-8 months) appeared driven by Mn, the second window (8-12 months) was driven by the metal mixture and dominated by Pb. A 1-unit increase in the mixture index was associated with a 0.7-unit increase in SD of anxiety symptoms. CONCLUSIONS: Childhood behaviors may demonstrate postnatal windows of susceptibility to individual and mixed metal concentrations measured in deciduous teeth. Prenatal dentine Mn may be protective, while excessive early postnatal Mn may increase risk for adverse behaviors. In combination, higher concentrations of Mn, Zn and Pb may have an adverse impact on behavior.

Use of di(2-ethylhexyl) phthalate-containing medical products and urinary levels of mono(2-ethylhexyl) phthalate in neonatal intensive care unit infants.

OBJECTIVE: Di(2-ethylhexyl) phthalate (DEHP) is a plasticizer used in medical products made with polyvinyl chloride (PVC) plastic and may be toxic to humans. DEHP is lipophilic and binds noncovalently to PVC, allowing it to leach from these products. Medical devices containing DEHP are used extensively in neonatal intensive care units (NICUs). Among neonates in NICUs, we studied exposure to DEHP-containing medical devices in relation to urinary levels of mono(2-ethylhexyl) phthalate (MEHP), a metabolite of DEHP. DESIGN: We used a cross-sectional design for this study. PARTICIPANTS: We studied 54 neonates admitted to either of two level III hospital NICUs for at least 3 days between 1 March and 30 April 2003. MEASUREMENTS: A priori, we classified the infants' exposures to DEHP based on medical products used: The low-DEHP exposure group included infants receiving primarily bottle and/or gavage feedings; the medium exposure group included infants receiving enteral feedings, intravenous hyperalimentation, and/or nasal continuous positive airway pressure; and the high exposure group included infants receiving umbilical vessel catheterization, endotracheal intubation, intravenous hyperalimentation, and indwelling gavage tube. We measured MEHP in the infants' urine using automated solid-phase extraction/isotope dilution/high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Urinary MEHP levels increased monotonically with DEHP exposure. For the low-, medium-, and high-DEHP exposure groups, median (interquartile range) MEHP levels were 4 (18), 28 (58), and 86 ng/mL (150), respectively (p = 0.004). After adjustment for institution and sex, urinary MEHP levels among infants in the high exposure group were 5.1 times those among infants in the low exposure group (p = 0.03). CONCLUSION: Intensive use of DEHP-containing medical devices in NICU infants results in higher exposure to DEHP as reflected by elevated urinary levels of MEHP.

Determining prenatal, early childhood and cumulative long-term lead exposure using micro-spatial deciduous dentine levels.

The aim of this study was to assess the validity of micro-spatial dentine lead (Pb) levels as a biomarker for accurately estimating exposure timing over the prenatal and early childhood periods and long-term cumulative exposure to Pb. In a prospective pregnancy cohort sub-sample of 85 subjects, we compared dentine Pb levels measured using laser ablation-inductively coupled plasma mass spectrometry with Pb concentrations in maternal blood collected in the second and third trimesters, maternal bone, umbilical cord blood, and childhood serial blood samples collected from the ages of 3 months to ≥6 years. We found that Pb levels (as 208Pb:43Ca) in dentine formed at birth were significantly associated with cord blood Pb (Spearman ρ = 0.69; n = 27; p<0.0001). The association of prenatal dentine Pb with maternal patella Pb (Spearman ρ = 0.48; n = 59; p<0.0001) was stronger than that observed for tibia Pb levels (Spearman ρ = 0.35; n = 41; p<0.03). When assessing postnatal exposure, we found that Pb levels in dentine formed at 3 months were significantly associated with Pb concentrations in children's blood collected concurrently (Spearman ρ = 0.64; n = 55; p<0.0001). We also found that mean Pb concentrations in secondary dentine (that is formed from root completion to tooth shedding) correlated positively with cumulative blood lead index (Spearman ρ = 0.38; n = 75; p<0.0007). Overall, our results support that micro-spatial measurements of Pb in dentine can be reliably used to reconstruct Pb exposure timing over the prenatal and early childhood periods, and secondary dentine holds the potential to estimate long-term exposure up to the time the tooth is shed.

Lead exposure and fear-potentiated startle in the VA Normative Aging Study: a pilot study of a novel physiological approach to investigating neurotoxicant effects.

BACKGROUND: Physiologically-based indicators of neural plasticity in humans could provide mechanistic insights into toxicant actions on learning in the brain, and perhaps prove more objective and sensitive measures of such effects than other methods. OBJECTIVES: We explored the association between lead exposure and classical conditioning of the acoustic startle reflex (ASR)-a simple form of associative learning in the brain-in a population of elderly men. Fifty-one men from the VA Normative Aging Study with cumulative bone lead exposure measurements made with K-X-Ray-Fluorescence participated in a fear-conditioning protocol. RESULTS: The mean age of the men was 75.5years (standard deviation [sd]=5.9) and mean patella lead concentration was 22.7µg/g bone (sd=15.9). Baseline ASR eyeblink response decreased with age, but was not associated with subsequent conditioning. Among 37 men with valid responses at the end of the protocol, higher patella lead was associated with decreased awareness of the conditioning contingency (declarative learning; adjusted odds ratio [OR] per 20µg/g patella lead=0.91, 95% confidence interval [CI]: 0.84, 0.99, p=0.03). Eyeblink conditioning (non-declarative learning) was 0.44sd less (95% CI: -0.91, 0.02; p=0.06) per 20µg/g patella lead after adjustment. Each result was stronger when correcting for the interval between lead measurement and startle testing (awareness: OR=0.88, 95% CI: 0.78, 0.99, p=0.04; conditioning: -0.79sd less, 95% CI: -1.56, 0.03, p=0.04). CONCLUSIONS: This initial exploration suggests that lead exposure interferes with specific neural mechanisms of learning and offers the possibility that the ASR may provide a new approach to physiologically explore the effects of neurotoxicant exposures on neural mechanisms of learning in humans with a paradigm that is directly comparable to animal models.

Cumulative lead exposure and tooth loss in men: the normative aging study.

BACKGROUND: Individuals previously exposed to lead remain at risk because of endogenous release of lead stored in their skeletal compartments. However, it is not known if long-term cumulative lead exposure is a risk factor for tooth loss. OBJECTIVES: We examined the association of bone lead concentrations with loss of natural teeth. METHODS: We examined 333 men enrolled in the Veterans Affairs Normative Aging Study. We used a validated K-shell X-ray fluorescence (KXRF) method to measure lead concentrations in the tibial midshaft and patella. A dentist recorded the number of teeth remaining, and tooth loss was categorized as 0, 1-8 or > or = 9 missing teeth. We used proportional odds models to estimate the association of bone lead biomarkers with tooth loss, adjusting for age, smoking, diabetes, and other putative confounders. RESULTS: Participants with > or = 9 missing teeth had significantly higher bone lead concentrations than those who had not experienced tooth loss. In multivariable-adjusted analyses, men in the highest tertile of tibia lead (> 23 microg/g) and patella lead (> 36 microg/g) had approximately three times the odds of having experienced an elevated degree of tooth loss (> or = 9 vs. 0-8 missing teeth or > or = 1 vs. 0 missing teeth) as those in the lowest tertile [prevalence odds ratio (OR) = 3.03; 95% confidence interval (CI), 1.60-5.76 and OR = 2.41; 95% CI, 1.30-4.49, respectively]. Associations between bone lead biomarkers and tooth loss were similar in magnitude to the increased odds observed in participants who were current smokers. CONCLUSION: Long-term cumulative lead exposure is associated with increased odds of tooth loss.