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BACKGROUND: Toenails are promising biomarkers of long-term metal exposure in epidemiological studies, but their accuracy may be compromised by systematic and random errors associated with heterogeneous toenail sample masses, as well as by substantial variability across laboratory batches. OBJECTIVES: We propose a novel modeling approach to calibrate toenail metal concentrations for the heterogeneity in sample masses and the variability between batches. METHODS: We developed a heteroscedastic spline mixed model relating sample mass and laboratory batch with measured concentrations, allowing for an average bias in measurements over all batches as a smooth function of sample mass, random variation in mass-related biases across batches, and mass-related heterogeneity in within-batch error variance. The model allowed partitioning the total variance of measured concentrations into the extraneous variances (due to different sample masses and laboratory batches) and the intrinsic variance (resulting from distinct metal exposures). We derived calibrated metal concentrations from the model by removing both sources of extraneous variation and estimating the predicted concentrations had all toenail samples been analyzed in a single batch and of the same mass. We provide the R script COMET (COrrected METals) to fit the proposed model, extract variance components, and calibrate metal concentrations. RESULTS: In a multicase-control study in Spain (MCC-Spain) with toenail determinations for 16 metals in 4,473 incident cases of five common cancers and 3,450 population controls, sample mass and batch accounted for 26%-60% of the total variance of measured concentrations for most metals. In comparison with calibrated concentrations, odds ratios for measured concentrations were biased by >10% toward or away from the null in onequarter of the estimated metal-cancer associations. DISCUSSION: The proposed model allows correcting toenail metal concentrations for sample mass heterogeneity and between-batch variability and could be applied to other biological specimens of heterogeneous size, distinct laboratory techniques, and different study designs.

Toenails are promising biomarkers of long-term metal exposure in epidemiological studies, but their accuracy may be compromised by systematic and random errors associated with heterogeneous toenail sample masses, as well as by substantial variability across laboratory batches. We propose a novel modeling approach to calibrate toenail metal concentrations for the heterogeneity in sample masses and the variability between batches. We developed a heteroscedastic spline mixed model relating sample mass and laboratory batch with measured concentrations, allowing for an average bias in measurements over all batches as a smooth function of sample mass, random variation in mass-related biases across batches, and mass-related heterogeneity in within-batch error variance. The model allowed partitioning the total variance of measured concentrations into the extraneous variances (due to different sample masses and laboratory batches) and the intrinsic variance (resulting from distinct metal exposures). We derived calibrated metal concentrations from the model by removing both sources of extraneous variation and estimating the predicted concentrations had all toenail samples been analyzed in a single batch and of the same mass. We provide the R script COMET (COrrected METals) to fit the proposed model, extract variance components, and calibrate metal concentrations. In a multicase-control study in Spain (MCC-Spain) with toenail determinations for 16 metals in 4,473 incident cases of five common cancers and 3,450 population controls, sample mass and batch accounted for 26%-60% of the total variance of measured concentrations for most metals. In comparison with calibrated concentrations, odds ratios for measured concentrations were biased by toward or away from the null in one-quarter of the estimated metal-cancer associations. The proposed model allows correcting toenail metal concentrations for sample mass heterogeneity and between-batch variability and could be applied to other biological specimens of heterogeneous size, distinct laboratory techniques, and different study designs. https://doi.org/10.1289/EHP14784.

Ingrown toenails (IGTN) are a prevalent, debilitating nail disorder that occurs when the edge of the nail plate grows abnormally to penetrate the periungual dermis. Multiple risk factors have been identified in the etiology. In this study, we aimed to investigate the risk factors that predispose patients to IGTN. This prospective, case-control study consisted of 130 patients with IGTN and 130 age- and sex-matched controls. The sociodemographic data, clinical features, and predisposing factors were questioned. Multivariate logistic regression (Enter and Forward: LR) analysis was applied to determine the risk factors related to IGTN. The IGTN group comprised 63 (48.5%) females and 67 (51.5%) males with a median age of 31 (IQR = 28.25) years. The most common type of IGTN in the study group was distal-lateral ingrowing in 115 (88.5%) patients. The median duration of IGTN was 5.5 (IQR = 10) months. In the multivariate regression analyses, the presence of improper nail trimming (OR: 7.063; 95% CI: 3.604–13.843), presence of hyperhidrosis (OR: 2.648; 95% CI: 1.198–5.853), poor foot hygiene (OR: 4.873; 95% CI: 2.271–10.456), presence of foot/toe deformity (OR: 5.413; 95% CI: 1.508–19.427), presence of increased curvature of the nails (OR: 2.588; 95% CI: 1.024–6.543), presence of onychomycosis (OR: 3.506; 95% CI: 1.267–9.705), increase in BMI (OR: 1.126; 95% CI: 1.038–1.221) were found to be the predisposing factors that increased the risk of IGTN. Improper nail trimming, hyperhidrosis, poor foot hygiene, onychomycosis, increased curvature of the nails, foot/toe deformity and increase in BMI were found to contribute significantly to the etiopathogenesis of the disease. Considering that most of these risk factors were modifiable, informing the public about risk factors will reduce the frequency of IGTN, and modifying risk factors in patients will enable rapid control of the disease and reduce recurrences.

Potentially harmful elements (PHEs) manganese (Mn), cobalt (Co), copper (Cu), lead (Pb), nickel (Ni) and zinc (Zn) were measured in human hair/nails, staple crops and drinking water to ascertain the level of exposure to dust transference via wind and rain erosion for members of the Mugala community living near a mine waste dump in the Zambian Copperbelt. The mean PHE concentrations of hair in decreasing order were Zn (137 ± 21 mg/kg), Cu (38 ± 7 mg/kg), Mn (16 ± 2 mg/kg), Pb (4.3 ± 1.9 mg/kg), Ni (1.3 ± 0.2 mg/kg) and Cr (1.2 ± 0.2 mg/kg), Co (0.9 ± 0.2 mg/kg) and Cd (0.30 ± 0.02 mg/kg). Whilst for toenails the decreasing order of mean concentrations was Zn (172 ± 27 mg/kg), Cu (30 ± 5 mg/kg), Mn (12 ± 2 mg/kg), Pb (4.8 ± 0.5 mg/kg), Ni (1.7 ± 0.14 mg/kg) and Co (1.0 ± 0.02 mg/kg), Cr (0.6 ± 0.1 mg/kg) and Cd (0.1 ± 0.002 mg/kg). The concentration of these potentially harmful elements (PHEs) varied greatly among different age groups. The results showed that Mn, Co, Pb, Cd and Zn were above the interval values (Biolab in Nutritional and environmental medicine, Hair Mineral Analysis, London, 2012) at 0.2–2.0 mg/kg for Mn, 0.01–0.20 mg/kg for Co, < 2.00 mg/kg for Pb, < 0.10 mg/kg for Cd and 0.2–2.00 mg/kg for Zn, whilst Ni, Cu and Cr concentrations were within the normal range concentrations of < 1.40 mg/kg, 10–100 mg/kg and 0.1–1.5 mg/kg, respectively. Dietary intake of PHEs was assessed from the ingestion of vegetables grown in Mugala village, with estimated PHE intakes expressed on a daily basis calculated for Mn (255), Pb (48), Ni (149) and Cd (33) µg/kg bw/day. For these metals, DI via vegetables was above the proposed limits of the provisional tolerable daily intakes (PTDIs) (WHO in Evaluation of certain food additive and contaminants, Seventy-third report of the Joint FAO/WHO Expert Committee on Food Additives, 2011) for Mn at 70 µg/kg bw/day, Pb at 3 µg/kg bw/day, Ni and Cd 5 µg/kg bw/day and 1 µg/kg bw/day, respectively. The rest of the PHEs listed were within the PTDIs limits. Therefore, Mugala inhabitants are at imminent health risk due to lead, nickel and cadmium ingestion of vegetables and drinking water at this location.

Background Hallux Valgus (HV) deformity is associated with misalignment in the sagittal plane that affects the first toe. However, the repercussions of the first toe hyperextension in HV have been scarcely considered. The purpose of this study was to provide evidence of the association between first-toe hyperextension and the risk of first toenail onycholysis in HV. Methods A total of 248 HV from 129 females were included. The extension of 1st MTP joint was measured while the patient was in the neutral position of the hallux using a two-branch goniometer. The classification of the HV severity stage was determined by the Manchester visual scale, and the height of the first toe in the standing position was measured using a digital meter. An interview and clinical examination were performed to collect information on the presence of onycholysis of the first toe. Results Of the 248 HV studied, 100 (40.3%) had onycholysis. A neutral extension > 30 degrees was noted in 110 (44.3%) HV. The incidence of onycholysis was higher in HV type C than in type B ( p  = 0.044). The probability of suffering onycholysis in the right foot was 2.3 times greater when the neutral position was higher than 30 degrees (OR = 2.3; p  = 0.004). However, this was not observed in the left foot ( p  = 0.171). Onycholysis was more frequent in HV with more than 2 cm height of the first toe ( p  < 0.001). For both feet, the probability of suffering onycholysis was greater for each unit increase in hallux height (right foot OR = 9.0402, p  = 0.005; left foot OR = 7.6633, p  = 0.010). Conclusions The incidence of onycholysis appears to be significantly associated with HV showing more than 30º extension, and more than 2 cm height of the first toe. Height and hyperextension of the first toe together with first toenail pathology should be mandatory in the evaluation of HV.

Autism spectrum disorder (ASD) has become a global public health concern, impacting the quality of life. The question of gene-environment interaction in the emergence of ASD remains a subject of ongoing debate, and exploring its pathophysiology is thoroughly related to metals as a risk factor. Therefore, this study aims to assess the levels of toxic (Al, Cd, Hg, and Pb) and essential (Cr, Mn, Fe, Ni, Cu, Zn, and Se) elements in toenail samples collected in children with ASD and neurotypical children, by ICP-MS. Parallelly, we will discuss the use of toenails as an exposure indicator. The study involved 208 children aged 3 to 14 from Marrakech, Morocco. One hundred two were diagnosed with ASD and 106 were neurotypical children. Significant statistical differences in the concentration of Cr, Mn, and Fe were documented between the two groups. Higher levels of Pb in toenails compared to reference values have been reported. No association was established between concentrations of elements and age. Spearman correlation coefficients revealed a significantly different pattern of mutual dependence for toxic and essential elements between the two groups. The strongest positive correlations were found in the neurotypical group (Fe–Mn ( ρ  = 0.750), and Se–Zn ( ρ  = 0.800)). These results provide additional, although inconclusive, evidence on the probable role of element disturbance in the pathogenesis of ASD. Further studies should be performed to explore other nutritional, cultural, sociodemographic, environmental, and methodological factors that may impact the levels of these elements in the nails and their possible correlation with the incidence of ASD.

Human nails have recently become a sample of interest for toxicological purposes. Multiple studies have proven the ability to detect various analytes within the keratin matrix of the nail. The analyte of interest in this study is fentanyl, a highly dangerous and abused drug in recent decades. In this proof-of-concept study, ATR–FTIR was combined with machine learning methods, which are effective in detecting and differentiating fentanyl in samples, to explore whether nail samples are distinguishable from individuals who have used fentanyl and those who have not. PLS-DA and SVM-DA prediction models were created for this study and had an overall accuracy rate of 84.8% and 81.4%, respectively. Notably, when classification was considered at the donor level—i.e., determining whether the donor of the nail sample was using fentanyl—all donors were correctly classified. These results show that ATR–FTIR spectroscopy in combination with machine learning can effectively differentiate donors who have used fentanyl and those who have not and that human nails are a viable sample matrix for toxicology.

Manganese (Mn) is an essential nutrient; however, overexposure can be neurotoxic. Recent evidence suggests that exposure to Mn from drinking water could be neurotoxic; however, research is hampered by the lack of consensus on a reliable biomarker of Mn exposure. Naturally high concentrations of Mn can occur in groundwater, particularly for private, unregulated water systems. This study aimed to investigate the association between exposure to Mn from drinking water with a relatively low Mn content (median of 2.9 μg/L; range, undetectable–8,340 μg/L) and Mn in toenails from women collected at two time points: during and after pregnancy. Mn concentrations in the paired toenail samples gathered during the second to third trimester of pregnancy and 2 weeks postpartum were correlated (r = 0.47, p < 0.001, n = 596). Among women consuming drinking water Mn in the highest tertile (i.e., > 9.8 μg/L) significant positive correlations were found between water Mn and toenails Mn (r = 0.31 and r = 0.38, for toenail samples collected during pregnancy and postpartum, respectively), whereas little to no correlation was observed at lower water concentrations. Overall, our data suggest that maternal toenail samples are a reliable environmental Mn exposure biomarker and reflect exposure from drinking water.

BackgroundChildren residing in communities near metalworking industries are vulnerable to multiple toxic metal exposures. Understanding biomarkers of exposure to multiple toxic metals is important to characterize cumulative burden and to distinguish potential exposure sources in such environmental justice neighborhoods impacted by industrial operations. Exposure to metal mixtures has not been well-characterized among children residing in the United States, and is understudied in communities of color.MethodsIn this study we used toenail clippings, a noninvasive biomarker, to assess exposure to arsenic (As), cadmium (Cd), mercury (Hg), manganese (Mn), lead (Pb), antimony (Sb), selenium (Se), and vanadium (V). We used nonnegative matrix factorization (NMF) to identify “source” signatures and patterns of exposure among predominantly working class Latinx children residing near an industrial corridor in Southeast Los Angeles County. Additionally, we investigated the association between participant demographic, spatial, and dietary characteristics with identified metal signatures.ResultsThrough NMF, we identified three groupings (source factors) for the metal concentrations in children’s toenails. A grouping composed of Sb, Pb, As, and Cd, was identified as a potential industrial source factor, reflective of known airborne elemental emissions in the industrial corridor. We further identified a manganese source factor primarily composed of Mn, and a potential dietary source factor driven by Se and Hg. We observed differences in the industrial source factor by age of participants, while the dietary source factor varied by neighborhood.ConclusionUtilizing an unsupervised dimension reduction technique (NMF), we identified a “source signature” of contamination in toenail samples from children living near metalworking industry. Investigating patterns and sources of exposures in cumulatively burdened communities is necessary to identify appropriate public health interventions.

The aim was to assess the trace element contents in toenails of older adults and its association with regular physical activity. Cross-sectional multicentre study in Spain, collecting data from a random sample of 380 participants (54% female) aged 55-80 years (men) and 60-80 years (women) with no previously documented cardiovascular disease. Physical activity performed was measured using the Minnesota Leisure-time Physical Activity Questionnaire. The 25 most inactive and 25 most active individuals for each sex were selected for this study (final sample n = 100). Anthropometric measurements were performed and toenail samples collected for calcium (Ca), chromium (Cr), iron (Fe), cobalt (Co), nickel (Ni), zinc (Zn), selenium (Se) and mercury (Hg) analysis. Significant differences between sexes were reported in Ca concentrations, women having lower concentrations than men. No differences were reported in trace element contents between active and inactive men. Active women showed higher Ca, Cr, Fe, Co, and Zn and lower Hg contents than their inactive peers (all p<0.05). Inactive women showed lower Ca and Co levels (735.0 mg/kg and 4.5 μg/kg, respectively) than inactive men (1170.0 mg/kg and 7.9 μg/kg, respectively). Active women had lower Ca and higher levels of Cr (936.0 mg/kg and 1230.0 μg/kg, respectively) than active men (1070.0 mg/kg and 522.0 μg/kg, respectively). The present data added new information on the element contents in toenails of healthy Spanish older adults. The concentration of trace elements was similar in both sexes except for Ca which were lower in women. The trace element contents in women's toenails, but not in men, were markedly influenced by physical activity, with higher levels of Ca and Fe and lower Hg among active females.