Association between blood lead levels and markers of calcium homeostasis: a systematic review and meta-analysis.

Chronic Pb exposure associated systemic illness are partly posited to involve calcium homeostasis. Present systematic review aims to comprehensively evaluate the association between chronic lead exposure and markers of calcium homeostasis. Observational studies documenting the changes in calcium homeostasis markers (i.e. serum calcium, parathyroid hormone, vitamin D & calcitonin) between occupationally Pb exposed group and control group were systematically searched from pubmed-Medline, Scopus, and Embase digital databases since inception to September 24, 2021. The protocol was earlier registered at PROSPERO (ID: CRD42020199503) and executed adhering to PRISMA 2020 guidelines. Mean differences of calcium homeostasis markers between the groups were analysed using random-effects model. Conventional I2 statistics was employed to assess heterogeneity, while the risk for various biases were assessed using Newcastle Ottawa Scale. Sub-group, sensitivity and meta-regression analyses were performed where data permitted. Eleven studies including 837 Pb exposed and 739 controls were part of the present study. Pb exposed group exhibited higher mean blood lead level [i.e. 36.13 (with 95% CI 25.88-46.38) µg/dl] significantly lower serum calcium (i.e. - 0.72 mg/dl with 95% CI - 0.36 to - 1.07) and trend of higher parathyroid levels and lower vitamin D levels than controls. Heterogeneity was high (I2 > 90%) among the studies. Considering the cardinal role of calcium in multiple biological functions, present observations emphasis the need for periodic evaluation of calcium levels and its markers among those with known cumulative Pb exposure.

Blood lead levels and lead toxicity in children aged 1-5 years of Cinangka Village, Bogor Regency.

Lead is one of ten hazardous chemicals of public health concern and is used in more than 900 occupations, including the battery, smelting, and mining industries. Lead toxicity accounts for 1.5% (900,000) of deaths annually in the world. In Indonesia, reports of high Blood Lead Level (BLL) were associated with residency in Used Lead Acid Battery (ULAB) recycling sites. The present study aims to investigate the BLL and the evidence of lead toxicity of children living in an ULAB recycling site in Bogor Regency, Indonesia. A cross-sectional study involving 128 children aged 1-5 years was conducted in September-October 2019. The socio-economic factors, BLL, nutritional status, and hematological parameters, were evaluated. Data were analyzed by univariate and bivariate using the Chi-Square test. Socio-economic factors revealed only 2.3% children have pica and 10.9% children have hand-to-mouth habits. Majority of parents had low income, education, and have stayed in the village for years. Analysis on BLL revealed that 69.5% children had BLL of >10 µg/dL, 25% had abnormal BMI, 23.4% had underweight, 53.9% had stunting, 33.6% had anemia, and 22.6% had basophilic stippling. The average BLL and hemoglobin levels of respondents were 17.03 µg/dL and 11.48 g/dL, respectively. Bivariate analysis revealed that children with high BLL had double risk of having underweight and protected from stunting. Analysis on the association between BLL and BMI for age revealed a higher risk to have abnormal BMI. The high BLL also had 1.017 times risk of developing anemia, and almost doubled risk of having basophilic stippling, although they were not statistically significant. In conclusion, the high BLL of children living in the ULAB recycling indicates that lead exposure as well as lead toxicity are still occurring in Cinangka Village, and alerts to the need for a systematic action to mitigate the exposure.

Trend in blood lead levels in Taiwanese adults 2005-2017.

This study examined the trend of blood lead levels (BLLs) in Taiwanese adults and analyzed the variations in the BLL between Linkou (northern) and Kaohsiung (southern) hospital branches. Between 2005 and 2017, 3,804 adult participants received blood lead tests at the Linkou (n = 2,674) and Kaohsiung (n = 1,130) branches of Chang Gung Memorial Hospital. The geometric mean of BLL was 2.77 µg/dL. The adult participants from the Kaohsiung branch were not only age older (49.8±14.1 versus 39.4±14.2 years; P<0.001) and male predominant (65.8 versus 41.7%; P<0.001) but also showed a higher BLL (4.45±3.93 versus 2.82±2.42 µg/dL; P<0.001) and lower estimated glomerular filtration rate (87.62±25.94 versus 93.67±23.88; P<0.001) than those from the Linkou branch. Multivariable logistic regression analysis revealed that the Kaohsiung branch [odds ratio (OR): 7.143; 95% confident interval (CI): 5.682-8.929; P<0.001], older age (OR: 1.008; 95% CI: 1.000-1.015; P = 0.043) and reduced estimated glomerular filtration rate (OR: 1.009; 95% CI: 1.004-1.014; P = 0.001) were significant predictors for BLL > 5 µg/dL. Therefore, this study confirmed a continuous decreasing trend in the BLL in Taiwan after banning leaded petrol in 2000.

Relationship between personal-sampled air lead and blood lead in low-lead-exposure workers in Japan to apply multiple regression models determining permissible air lead concentration.

OBJECTIVES: We investigated the relationship between lead in air (Pb-A) measured by personal sampling and blood lead (Pb-B) in workers with relatively low lead exposure to estimate the permissible air concentration of lead corresponding to the biological tolerance value of Pb-B of 15 µg/dL. METHODS: We collected air samples at a lead-acid battery factory in Japan by personal sampling devices attached to 32 workers (19 males and 13 females) and measured Pb-A by a graphite furnace atomic absorption spectrophotometer in 2017-2020. In addition, we collected information on age, smoking habits, Pb-B, and urinary δ-aminolevulinic acid from the records of medical examinations for lead poisoning. Samples were collected two times from four workers, resulting in 36 data sets. RESULTS: Before analyses, we excluded four inappropriate data sets. The levels of Pb-A in the factory and Pb-B in the workers were almost under the current permissible limits. Multiple regression models showed significant correlations between Pb-B and Pb-A, and sex, and borderline significance between Pb-B and age. Based on them, we calculated Pb-A corresponding to Pb-B 15 µg/dL, and obtained similar values to the current occupational exposure limit (OEL) of 30 µg/m3 , with slight variation between sex and age. CONCLUSION: These results validate OEL, although supplementary conditions in terms of sex and age may be necessary.

Efficacy and expenses of succimer vs. d-penicillamine plus garlic in the treatment of lead poisoning: a retrospective cross-sectional study.

PURPOSE: Lead Poisoning is a major health problem in Iran. We aimed to compare efficacy of a standard regimen (Succimer) with that of a low-priced combination of D-penicillamine and Garlic in outpatients with lead poisoning. METHODS: In this retrospective cross-sectional study, year-long clinical files of outpatients with lead poisoning in two referral toxicology clinics in Mashhad, Iran were reviewed. A total of 79 patients (all men), received either Succimer or a combination of D-penicillamen plus garlic (DPN + Gar), for 19 and 30 days, respectively. Clinical and laboratory data, including blood lead level (BLL), were analyzed and treatment expanses were compared between the two regimens. RESULTS: Of 79 male patients, 42 were treated by DPN + Gar and 37 received Succimer. Mean BLL of DPN + Gar group before treatment (965.73 ± 62.54 µg/L) was higher than that of the Succimer group (827.59 ± 24.41) (p < 0.001). After treatment, BLL in both groups significantly reduced to 365.52 ± 27.61 µg/L and 337.44 ± 26.34 µg/L, respectively (p < 0.001). The price of a 19-day treatment with Succimer was approximately 28.6 times higher than a one-month course of treatment with garlic plus DPN. None of the treatments caused serious side effects in the patients. CONCLUSION: Combination therapy with DPN + Gar is as effective as Succimer in Pb poisoning, while treatment with Succimer is significantly more expensive.

Who to Test? A Retrospective Study of Lead Testing in High-Risk Children.

BACKGROUND: Nearly all pediatric patients in our setting meet high-risk criteria for lead exposure based on screening recommendations and guidelines. Implementation of screening and testing has been inconsistent. OBJECTIVE: To assess the utility and efficacy of performing universal lead testing between ages 1 and 5 at an urban academic pediatric practice. METHODS: Retrospective review of patients with routine lead testing between 2010 and 2015. Key variables included demographics, serum lead level, and behavioral diagnoses. RESULTS: A total of 6597 serum lead levels from 3274 patients were reviewed. Forty-seven samples (0.7%) from 24 patients (0.7%) were elevated. Of the 24 patients with elevated lead, 75% were identified at age 1 or 2. Sixty-seven percent of patients with first elevated lead level at age 3 or older had a diagnosis of developmental delay. CONCLUSION: Routine testing of high-risk patients yielded minimal specificity in identifying elevated lead levels, especially in patients older than 3 years and without developmental delay.

Association of blood lead levels with neurobehavior and BDNF expression in school going children.

BACKGROUND: Childhood Lead (Pb) toxicity has been an ongoing concern for decades; however, its underlying pathogenesis remains unclear. Although its prevalence has come down in developed countries (USA, Europe); it is relatively high in low to middle-income countries of South-East Asia. The current study aimed to evaluate the association of blood lead levels (BLLs) with neurobehavioral alterations and changes in Brain-Derived Neurotropic Factor (BDNF) expression in Indian school children. METHODOLOGY: School going children in age group of 9-15 years (N = 72) were included in the study. Neurobehavioral changes were assessed using Childhood Psychopathological Measurement Schedule (CPMS) and BLL were measured by Graphite Furnace Atomic Absorption Spectrophotometry (GFAAS). BDNF mRNA expression and serum BDNF levels were assessed by Real-Time PCR and ELISA, respectively. RESULTS: Median BLL was 4.95 µg/dL (IQR = 4.47), very close to the recommended toxic cut off levels (<5 µg/dL). BLLs had a direct correlation with both CPMS scores and BDNF expression. Depression was found to be significantly higher in boys than in girls with high BLLs. BDNF mRNA expression and serum BDNF levels were higher among children with high BLL, although not to significant levels. CONCLUSION: We report a significant association of neurobehavioral changes with the prevalence of high Pb levels in Indian children. Additionally significant correlation of BDNF with BLL in these children suggests a causal role of BDNF in Pb induced neurological damage.

Reassessment of the threshold of the blood lead level to increase urinary δ-aminolevulinic acid based on their relationship in recent lead workers in Japan.

OBJECTIVES: The present study investigated the quantitative relationship between blood lead (Pb-B) and urinary δ⁻aminolevulinic acid (ALA-U) in lead workers, and examined the Pb-B level that induces increases in ALA-U and the corresponding ALA-U. METHODS: We collected 10 562 data sets on Pb-B, ALA-U, age, and smoking habits from 808 workers (771 males and 37 females) who underwent multiple lead poisoning medical examinations at a lead-acid battery and lead smelting plant in Japan between 1995 and 2018. Females were excluded, and data collected in 169 subjects prior to engaging in lead work were used as the control. Pb-B and ALA-U levels were measured by graphite furnace atomic absorption spectrophotometry and high-performance liquid chromatography respectively. RESULTS: A significant dose-response relationship was observed between Pb-B and ALA-U based on Pb-B-classified observations of increases in ALA-U values and the prevalence of over-reference ALA-U as well as regression analyses independent of smoking habits. The results obtained revealed that the threshold of Pb-B to increase ALA-U was 25.1-35.0 µg/dL based on the significant elevation point of the prevalence of over-reference ALA-U and 16.2-22.3 µg/dL from a 3rd degree regression equation. CONCLUSIONS: We proposed a threshold of Pb-B to increase ALA-U of 20 µg/dL and a biologically acceptable value of ALA-U of 1 mg/L, corresponding to the threshold.

Decreased serum bilirubin levels in children with lead poisoning.

OBJECTIVE: Lead is a toxic heavy metal, which causes irreversible damage in children. Oxidative stress is the underlying mechanism of lead toxicity, and monitoring oxidative stress of lead poisoning children in vivo is important. Our study aimed to investigate blood serum levels of biochemical parameters, including albumin, bilirubin, creatinine, and uric acid, which are regarded as non-enzymatic antioxidants, in children with lead poisoning. METHODS: We studied 355 children with lead poisoning and 355 age- and sex-matched controls. We analyzed clinical characteristics and measured serum levels of total protein, globulin, albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase, urea, and creatinine. RESULTS: We found that albumin, bilirubin, urea, and creatinine levels were significantly lower and AST, total protein, and globulin levels were higher in children with lead poisoning than in controls. Direct bilirubin, albumin, total protein, urea, creatinine, and AST levels were associated with lead poisoning after adjustment for other covariates. Spearman analysis showed that direct bilirubin, albumin, and urea levels were independent indicators (i.e., not related to hemoglobin or weight), while creatinine levels showed a moderate correlation with weight. CONCLUSION: Lead interferes with the non-enzymatic antioxidant system in children, and lead poisoning results in a decrease in serum bilirubin levels.

Exploring persistent racial/ethnic disparities in lead exposure among American children aged 1-5 years: results from NHANES 1999-2016.

OBJECTIVE: The aim of this study was to determine whether long-standing racial disparities in lead exposure still exists for children age 1-5 years old. We examined if blood lead levels were higher among non-Hispanic Black children and others compared to non-Hispanic White children. METHODS: Data from the National Health and Nutrition Examination Survey (NHANES) from 1999-2016 were used. Geometric mean blood lead levels (BLLs) were compared by race/ethnicity using log-transformed simple linear regression. Associations between race and elevated BLL were assessed using weighted Chi-square tests. Log-transformed multiple weighted linear regression was used to assess what factors affected BLLs. RESULTS: A total of 6772 children were included in this study. In 1999-2000, the geometric mean BLL for non-Hispanic Black children was 3.08 µg/dL, compared to 2.03 µg/dL for non-Hispanic White children (p = 0.01). The difference in geometric mean BLL between non-Hispanic Black children and non-Hispanic White children continued to be statistically significant in later years (all p < 0.05) until 2015-2016 (0.89 µg/dL vs 0.74 µg/dL, p = 0.17). Log-transformed linear regression showed that being non-Hispanic Black and having low family income were independently associated with higher BLL. CONCLUSION: Although lead exposure in the general population continued to decline for all racial/ethnic groups, non-Hispanic Black children still had higher BLL than non-Hispanic White children. In more recent years, the racial/ethnic gap was lesser but persisted. Racial/ethnic disparity in childhood BLL could be partially explained by socio-economic factors.

A Rapid Mercury Droplet Electrode Polarography Method for Determination of Blood Lead Level in Lead Poisoned People.

BACKGROUND: Lead is a hazardous heavy metal, which causes many problems in the human body. Unfortunately, recent reports showed that smugglers and opium sellers add lead to drugs during the production procedure in order to increase its weight and cost. PURPOSE: The aim of this study was development of a rapid and accurate method for measurement of blood lead levels (BLL) in the oral and inhaled opiate abuser people. METHODS: BLL in samples obtained from the oral and inhaled opium addicted patients referring to Sina Hospital in Tabriz, Iran, during 2017 was compared with healthy control group (N=15). The wet digestion method was used to prepare whole blood and Mercury Droplet Electrode Polarography (MDEP) method was utilized for measurement of the lead content of digested samples. RESULTS: Results showed that there were significant differences between the BLL of samples obtained from oral (17.12±74.61 µg/dL, p<0.0003) and inhaled (19.33±2.257 µg/dL, p<0.0001) opium addicted groups in comparison with healthy control group (4.669±0.3367 µg/dL). CONCLUSION: Based on the results of this study it was observed that BLL in opium addicted people needs to be measured as soon as possible. Furthermore, screening of blood lead concentrations in opium-addicted people with a rapid and accurate MDEP method is very necessary and important.

Influence of VDR and HFE polymorphisms on blood lead levels of occupationally exposed workers.

Lead is a ubiquitous heavy metal toxin of significant public health concern. Every individual varies in their response to lead's toxic effects due to underlying genetic variations in lead metabolizing enzymes or proteins distributed in the population. Earlier studies, including our lab, have attributed the influence of ALAD (δ-Aminolevulinate dehydratase) polymorphism on blood lead retention and ALAD activity. The present study aimed to investigate the influence of VDR (Vitamin D receptor) and HFE (Hemochromatosis) polymorphisms in modulating blood lead levels (BLLs) of occupationally exposed workers. 164 lead-exposed subjects involved in lead alloy manufacturing and battery breaking and recycling processes and 160 unexposed controls with BLLs below 10 µg/dL recruited in the study. Blood lead levels, along with a battery of biochemical assays and genotyping, were performed. Regression analysis revealed a negative influence of BLLs on ALAD activity (p < 0.0001) and a positive influence on smokeless tobacco use (p < 0.001) in lead-exposed subjects. A predicted haplotype of the three VDR polymorphisms computed from genotyping data revealed that T-A-A haplotype increased the BLLs by 0.93 units (p ≤ 0.05) and C-C-A haplotype decreased the BLLs by 7.25 units (p ≤ 0.05). Further analysis revealed that the wild-type CC genotype of HFE H63D presented a higher median BLL, indicating that variant C allele may have a role in increasing the concentration of lead. Hence, the polymorphism of genes associated with lead metabolism might aid in predicting genetic predisposition to lead and its associated effects.

Lead exposure induces metabolic reprogramming in rat models.

Lead is a toxin of great public health concern affecting the young and aging population. Several factors such as age, gender, lifestyle, dose, and genetic makeup result in interindividual variations to lead toxicity mainly due to variations in metabolic consequences. Hence, the present study aimed to examine dose-dependent lead-induced systemic changes in metabolism using rat model by administering specific doses of lead such as 10 (low lead; L-Pb), 50 (moderate lead; M-Pb), and 100 mg/kg (high lead; H-Pb) body weight for a period of one month. Biochemical and haematological analysis revealed that H-Pb was associated with low body weight and feed efficiency, low total protein levels (p ≤ 0.05), high blood lead (Pb-B) levels (p ≤ 0.001), low ALAD (δ-aminolevulinate dehydratase) activity (p ≤ 0.0001), high creatinine (p ≤ 0.0001) and blood urea nitrogen (BUN) (p ≤ 0.01) levels, elevated RBC and WBC counts, reduced haemoglobin and blood cell indices compared to control. Spatial learning and memory test revealed that H-Pb exposed animals presented high latency to the target quadrant and escape platform compared to other groups indicating H-Pb alters cognition function in rats. Histopathological changes were observed in liver and kidney as they are the main target organs of lead toxicity. LC-MS analysis further revealed that Butyryl-L-carnitine (p ≤ 0.01) and Ganglioside GD2 (d18:0/20:0) (p ≤ 0.05) levels were significantly reduced in H-Pb group compared to all groups. Further, pathway enrichment analysis revealed abundance and significantly modulated metabolites associated with oxidative stress pathways. The present study is the first in vivo model of dose-dependent lead exposure for serum metabolite profiling.

Assessment of Bone Turnover Biomarkers in Lead-Battery Workers with Long-Term Exposure to Lead.

BACKGROUND: The major portion of lead in the body resides in skeletal system. The bone turnover affects the release of lead into the circulation from bones. The bone turnover biomarkers (BTM) in lead-battery workers with long-term exposure to lead have not been explored yet. OBJECTIVE: To evaluate the BTM (formation and resorption) in lead-battery workers with long-term exposure to lead in lead-battery manufacturing plant. METHODS: 176 male lead-exposed workers and 80 matched comparison group were studied. All participants were examined for blood lead levels (BLLs), bone formation biomarkers- serum osteocalcin (OC), alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP)-and bone resorption biomarkers-serum pyridinoline (PYD), deoxypyridinoline (DPYD), tartarate-resistant acid phosphatase-5b (TRACP-5b), and urinary hydroxyproline (UHYP). RESULTS: We found a significantly higher bone formation biomarkers such as BALP (p=0.007) and bone resorption biomarkers, eg, PYD (p=0.048), TRCAP-5b (p=0.001), and UHYP (p=0.001) in lead-exposed workers. A significant (p=0.041) negative correlation (ρ ­0.128) was noted between BLLs and OC. A significant positive correlation was noted between BLLs and TRACP-5b (ρ 0.176, p=0.005) and UHYP (ρ 0.258, p=0.004). Serum OC (p=0.040) and UHYP (p=0.015) levels changed significantly with BLL level. Bone resorption biomarkers levels- PYD, TRACP-5b, and BALP-were higher among those with higher BLLs levels. The duration of exposure was significantly associated with BALP (p=0.037), DPYD (p=0.016), TRACP-5b (p=0.001), and UHYP (p=0.002) levels. CONCLUSION: Long-term lead exposure affects the bone turnover.

Identification of the origin of infantile saturnism based on lead isotopic and elemental ratios.

BACKGROUND: In France, the prevalence of childhood lead poisoning is becoming rare since the avoidance of lead in paints in 1949 and the gradual replacement of water pipes. Chronic lead toxicity is well known and is well correlated to blood lead concentration. AIM: Here we report a case of severe lead poisoning occurring in a young female child with a pica behavior. METHODS: A blood sample and four environmental samples were analyzed using inductively coupled plasma- mass spectrometry (ICP-MS). Lead concentration, lead isotopes and elemental ratios were compared. RESULTS: The determination of 208Pb/206Pb, 206Pb/207Pb and Cd/Pb has allowed us to identify the origin of lead poisoning. DISCUSSION-CONCLUSION: The source of contamination was eliminated and the child benefited from a psychological and medical follow up. Her outcome was positive. This case illustrated the potential interest of the use of elemental and isotopic ratios for clinical practice as the ICP-MS measurement has allowed a quick response and a rapid eviction of the contamination's source.

A Preliminary Report on the Largest Ongoing Outbreak of Lead Toxicity in Iran.

No countrywide data exists on the patients' characteristics of lead exposure in Iran. We aimed to evaluate the demographic characteristics and blood lead level (BLL) of these patients in the country scale during five consecutive years, including the epidemic outbreak year (2016). Between 2014 and 2018, records of all patients who had referred to two reference laboratories in Tehran, Iran, to check BLL were evaluated. Of 58,642 patients, 48,589 were male. Mean age was 44.9 ± 20.7 years. Males had higher BLLs and were significantly older. Median BLL was 16 µg/dL (0.3 to 263 µg/dL). Median BLL was significantly higher in 45- to 60-year-old patients. The highest median BLL was reported in May 2016 confirming our records about the peak of the epidemic. Although the frequency of high BLL declined after 2016, it never returned to the measures before that. Considering the ongoing high prevalence of increased BLLs after 2016 and similar environmental and occupational exposures as before, lead-contaminated opium still seems to persist in the Iranian opium black market. Substitution of this lead-contaminated opium by Opioid Maintenance Therapy (OMT)-prescribed opium tincture is recommended.

Relationship between blood test values and blood lead (Pb) levels in Black-headed gull (Chroicocephalus ridibundus: Laridae).

Few studies have evaluated immunosuppression due to lead accumulation below the overt toxicity threshold. If low levels of lead accumulation cause immunosuppression in birds, those birds could become more susceptible to pathogens. We aimed to determine if low levels of lead accumulation lead to immunosuppression in Black-headed gulls (Chroicocephalus ridibundus). Gulls were captured in Tokyo-bay and Mikawa-bay from January to April 2019. Their blood samples were analyzed for eight items. The data were analyzed to evaluate the correlation between lead concentrations and the variables from each bay. Lead was positively correlated with the percentage of heterophils and heterophil and lymphocyte ratio and negatively with lymphocytes. Thus, low lead accumulation levels may induce changes in percentage of the heterophils and lymphocyte.