Hearing Loss and Urinary trans,trans-Muconic Acid (t,t-MA) in 6- to 19-Year-Old Participants of NHANES 2017-March 2020.

Hearing loss (HL) is associated with poorer language development and school performance. Ototoxic substances such as metals and solvents, including benzene, are a risk factor associated with HL. This study examines potential associations between the benzene metabolite trans,trans-muconic acid (t,t-MA) and HL in youth of the National Health and Nutrition Examination Survey (NHANES). Logistic regression calculated adjusted odds ratio (aOR) associations between HL and urinary t,t-MA quartiles, natural-log transformed, and doubled urinary t,t-MA. Hearing threshold pure-tone average (PTA) at speech frequencies (SF) 0.5, 1, 2, and 4 kHz and high frequencies (HF) 3, 4, and 6 kHz were analyzed for slight HL (PTA > 15 dB) and mild HL (PTA > 20 dB). Urinary t,t-MA was statistically significantly associated with both slight SF and HF HL. For each doubling of t,t-MA there were increased odds of having slight SFHL (aOR = 1.42; 95% CI: 1.05, 1.92), slight HFHL (aOR = 1.31; 95% CI: 1.03, 1.66), mild SFHL (aOR = 1.60; 95% CI: 1.10, 2.32), and mild HFHL (aOR = 1.45; 95% CI: 1.03, 2.04). To our knowledge, this is the first population-based report of an association between SFHL, HFHL, and the benzene metabolite t,t-MA in youth 6 to 19 years old.

TERT-independent telomere elongation and shelterin dysregulation after pulmonary exposure to stainless-steel welding fume in-vivo.

Telomeres are inert DNA sequences (TTAGGG) at the end of chromosomes that protect genetic information and maintain DNA integrity. Emerging evidence has demonstrated that telomere alteration can be closely related to occupational exposure and the development of various disease conditions, including cancer. However, the functions and underlying molecular mechanisms of telomere alteration and shelterin dysregulation after welding fume exposures have not been broadly defined. In this study, we analyzed telomere length and shelterin complex proteins in peripheral blood mononuclear cells (PBMCs) and in lung tissue recovered from male Sprague-Dawley rats following exposure by intratracheal instillation (ITI) to 2 mg/rat of manual metal arc-stainless steel (MMA-SS) welding fume particulate or saline (vehicle control). PBMCs and lung tissue were harvested at 30 d after instillation. Our study identified telomere elongation and shelterin dysregulation in PBMCs and lung tissue after welding fume exposure. Mechanistically, telomere elongation was independent of telomerase reverse transcriptase (TERT) activation. Collectively, our findings demonstrated that welding fume-induced telomere elongation was (a) TERT-independent and (b) associated with shelterin complex dysregulation. It is possible that an alteration of telomere length and its regulatory proteins may be utilized as predictive biomarkers for various disease conditions after welding fume exposure. This needs further investigation.

Perfluoroalkyl acids, hyperuricemia and gout in adults: Analyses of NHANES 2009-2014.

BACKGROUND: Previous studies have reported a positive association of perfluoralkyl acids (PFAAs), including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), with hyperuricemia. The objective of the study is to investigate whether there is an association between concurrent serum levels of several PFAAs and gout, serum uric acid (SUA) or hyperuricemia in the U.S. adult population as represented by the National Health and Nutrition Examination Survey (NHANES) 2009-2014 sample (n = 4917). The PFAAs investigated include PFOA, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), perfluorohexane sulfonic acid (PFHxS) and PFOS. METHODS: This cross-sectional study used multivariate logistic regressions to analyze the association of single PFAAs with hyperuricemia and self-reported gout; the association with SUA was analyzed by multivariate linear regression. Analyses were adjusted for race/ethnicity, age, sex, education, alcohol consumption, smoking, serum cotinine, BMI, diabetes, hypertension, chronic kidney disease, and SUA (for gout only). RESULTS: Higher quartile values of serum PFOA and PFHxS were associated with increased odds of self-reported gout. There was a positive association of SUA with increased levels of PFOA, PFNA, PFOS, PFHxS and PFDA. Higher quartile values of PFOA, PFNA, and PFHxS were associated with higher odds of hyperuricemia. CONCLUSIONS: In this population-based cross-sectional analysis, we found an association between selected PFAAs and self-reported gout. We also confirmed previous reports of an association between several PFAAs and hyperuricemia. Our study suggests that exposure to PFAAs may be a risk factor for hyperuricemia and gout.

Perfluoroalkyl substances and anthropomorphic measures in children (ages 3-11 years), NHANES 2013-2014.

BACKGROUND: Perfluoroalkyl acids (PFAAs) are man-made compounds that are persistent in the environment and highly bioaccumulative in the body. Humans are exposed to a mixture of these substances, and the effects of these mixtures may be different than the effects noted for individual compounds. Prenatal exposure to PFAAs has been associated with decreased birth weight. The objective of the present study is to evaluate concurrent serum PFAA levels, as single compounds and as mixtures, in relation to anthropomorphic measures in children. METHODS: Using multivariate linear regression, we evaluated the association between single or PFAA mixtures and with height-for-age (HAZ), weight-for-age (WAZ), and BMI (BMIZ) z-scores in children (ages 3-11 years) participants of the National Health and Nutrition Examination Survey (NHANES) 2013-2014. Analyses were also stratified by sex. The PFAA mixture was based on relative potency factors express in terms of PFOA equivalency (CmixRPFi) or as molar sum of the PFAA congeners (∑molPFAA). RESULTS: There was a statistically significant association of PFHxS and PFOS with decreased HAZ in boys. The significantly decreased HAZ in boys was also found when the PFAAs were analyzed as mixtures: CmixRPFi (ß = -0.33; 95%CI: 0.63, -0.04) or ΣmolPFAAs (ß = -0.30; 95%CI: 0.56, -0.04). In boys, PFHxS was also associated with decreased WAZ and BMIZ. The only statistically significant association found in girls was between decreased HAZ and PFHxS. CONCLUSIONS: We found sex differences in the association between concurrent serum PFAA levels and anthropomorphic measures in children 3-11 years old. PFAA levels, as single congeners or as mixture concentrations were associated with decreased height-for-age z-score in boys.

Evaluation of ATSDR's MRL and EPA's RfCs/RfDs: Similarities, Differences, and Rationales.

Objectives: The Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA) derive minimal risk levels (MRLs) and reference concentrations and doses (RfCs and RfDs), respectively, for environmental contaminants to help identify potential health risks to exposed populations. MRLs, RfDs, and RfCs involve similar derivation methods, but the values sometimes differ for the same chemical. The objectives of this manuscript are to quantitatively assess similarities and differences between MRLs, RfCs, and RfDs, qualitatively describe how a number of factors can influence the development of the health guidance values (HGVs) and identify ongoing collaborations and opportunities for increased coordination of efforts. Materials and Methods: We collected MRLs and RfCs/RfDs, assessment date, and description of the derivation process from ATSDR's toxicological profiles and EPA's Integrated Risk Information System (IRIS) and Office of Pesticide Program (OPP) and identified reasons for differences between MRLs and RfCs/RfDs. Results: The most frequent types of differences in values that we found in our analysis included use of different methodologies, use of different studies, and/or completion of a more recent chemical evaluation. These can stem from differences in scientific judgement. Conclusion: To avoid confusion when disparate HGVs occur between government agencies, a keen understanding of these differences can be helpful for appropriate risk characterization and communication when applying HGVs.

Windows of sensitivity to toxic chemicals in the development of reproductive effects: an analysis of ATSDR's toxicological profile database.

Development of the fetus is a complex process influenced by many factors including genetics, maternal health, and environmental exposures to toxic chemicals. Adverse developmental effects on the reproductive system have the potential to harm generations beyond those directly exposed. Here, we review the available literature in Agency for Toxic Substances and Disease Registry toxicological profiles related to reproductive-developmental effects in animals following in utero exposure to chemicals. We attempt to identify windows of sensitivity. In the discussion, we correlate the findings with human development. The endpoints noted are fertility, estrus, anogenital distance, sex ratio, spermatogenesis, and mammary gland development. We identified some windows of sensitivity; however, the results were hampered by chronic-exposure studies designed to detect effects occurring throughout developmental, including multi-generational studies. This paper demonstrates the need for more acute studies in animals aimed at understanding time periods of development that are more susceptible to chemically induced adverse effects.

Historical View on Lead: Guidelines and Regulations.

Lead has been used in many commodities for centuries. As a result, human exposure has occurred through the production and use of these lead-containing products. For example, leaded gasoline, lead-based paint, and lead solder/pipes in water distribution systems have been important in terms of exposure potential to the general population. Worker exposures occur in various industrial activities such as lead smelting and refining, battery manufacturing, steel welding or cutting operations, printing, and construction. Some industrial locations have also been a source of exposure to the surrounding communities. While the toxicity of relatively high lead exposures has been recognized for centuries, modern scientific studies have shown adverse health effects at very low doses, particularly in the developing nervous system of fetuses and children. This chapter reflects on historical and current views on lead toxicity. It also addresses the development and evolution of exposure prevention policies. As discussed here, these lead policies target a variety of potential exposure routes and sources. The changes reflect our better understanding of lead toxicity. The chapter provides lead-related guidelines and regulations currently valid in the U. S. and in many countries around the world. The reader will learn about the significant progress that has been made through regulations and guidelines to reduce exposure and prevent lead toxicity.

DDT/DDE and breast cancer: a meta-analysis.

The biological basis for investigating dichlorodiphenyltrichloroethane (DDT) exposure and breast cancer risk stems from in vitro and animal studies indicating that DDT has estrogenic properties. The objective of this study was to update a meta-analysis from 2004 which found no association between dichlorodiphenyldichloroethylene (DDE) and breast cancer. We searched PubMed and Web of Science for studies published through June 2012 assessing DDT/DDE exposure and breast cancer. Summary Odds Ratios (ORs) with 95% confidence intervals (CIs) were calculated for the prevalence of breast cancer in the highest versus the lowest exposed groups for DDT and DDE. Difference of means of exposure for cases versus controls was analyzed for DDT and DDE. From the 500 studies screened, 46 were included in the meta-analysis. Slightly elevated, but not statistically significant summary ORs were found for DDE (1.05; 95% CI: 0.93-1.18) and DDT (1.02; 95% CI: 0.92-1.13). Lipid adjusted difference of means analysis found a significantly higher DDE concentration in cases versus controls (11.30 ng/g lipid; p=0.01). No other difference of means analysis found significant relationships. The existing information does not support the hypothesis that exposure to DDT/DDE increases the risk of breast cancer in humans.

Association of low-level blood lead and blood pressure in NHANES 1999-2006.

This study investigated whether low blood-lead levels (≤10 µg/dL) were associated with blood pressure (BP) outcomes. The authors analyzed data from National Health and Nutrition Examination Survey 1999-2006 and participants aged 20 years or older. Outcome variables were systolic and diastolic BP measurements, pulse pressure, and hypertension status. Multivariable linear and logistic regressions stratified by race/ethnicity and gender were performed. Blood lead levels (BLL) were significantly correlated with higher systolic BP among black men and women, but not white or Mexican-American participants. BLLs were significantly associated with higher diastolic BPs among white men and women and black men, whereas, a negative association was observed in Mexican-American men that had, also, a wider pulse pressure. Black men in the 90th percentile of blood lead distribution (BLL≥3.50 µg/dL) compared to black men in the 10th percentile of blood lead distribution (BLL≤0.7 µg/dL) had a significant increase of risk of having hypertension (adjusted POR=2.69; 95% CI: 1.08-6.72). In addition, blood cadmium was significantly associated with hypertension and systolic and diastolic blood. This study found that, despite the continuous decline in blood lead in the U.S. population, lead exposure disparities among race and gender still exist.

Metal ions affecting the hematological system.

Many metals are essential elements and necessary for proper biological function at low intake levels. However, exposure to high intake levels of these metals may result in adverse effects. In addition, exposures to mixtures of metals may produce interactions that result in synergistic or antagonistic effects. This chapter focuses on metals that affect the hematological system and how exposures to mixtures of metals may contribute to their hematotoxicity. Exposure to arsenic, cadmium, copper, lead, mercury, tin or zinc has been shown to produce some effect on the hematological system. Binary interactions resulting from exposure to combinations of metals may increase or decrease the hematotoxicity induced by individual metals. For example, copper, iron, and zinc have been shown to have a protective effect on the hematotoxicity of lead. In contrast, co-exposure to manganese may increase the hematotoxicity of lead.

Metal ions affecting the neurological system.

Several individual metals including aluminum, arsenic, cadmium, lead, manganese, and mercury were demonstrated to affect the neurological system. Metals are ubiquitous in the environment. Environmental and occupational exposure to one metal is likely to be accompanied by exposure to other metals, as well. It is, therefore, expected that interactions or "joint toxic actions" may occur in populations exposed to mixtures of metals or to mixtures of metals with other chemicals. Some metals seem to have a protective role against neurotoxicity of other metals, yet other interactions may result in increased neurotoxicity. For example, zinc and copper provided a protective role in cases of lead-induced neurotoxicity. In contrast, arsenic and lead co-exposure resulted in synergistic effects. Similarly, information is available in the current literature on interactions of metals with some organic chemicals such as ethanol, polychlorinated biphenyls, and pesticides. In depth understanding of the toxicity and the mechanism of action (including toxicokinetics and toxicodynamics) of individual chemicals is important for predicting the outcomes of interactions in mixtures. Therefore, plausible mechanisms of action are also described.

Alkyllead compounds and their environmental toxicology.

Alkyllead compounds are man-made compounds in which a carbon atom of one or more organic molecules is bound to a lead atom. Tetraethyllead and tetramethyllead are the most common alkyllead compounds that were used primarily as gasoline additives for many years. Consequently, auto emissions have accounted for a major part of lead environmental pollution. Alkyllead compounds can readily enter living organisms as they are well absorbed via all major routes of entry. Because of their lipid solubility, the alkylleads can also readily cross the blood-brain barrier. The toxicokinetic information on organic lead can be used as biomarkers of exposure for monitoring exposed individuals. The organic alkyllead compounds are more toxic than the inorganic forms of lead. Neurotoxicity is the predominant effect of lead (both for organic and inorganic forms), although lead affects almost every organ of the body. The use of alkyllead compounds has declined over the last 20 years, due to the worldwide effort to eliminate the use of leaded gasoline. This achievement can be viewed as a great accomplishment of public health preventive measures.

The role of exposure versus body burden data in deriving health guidance values.

The Agency for Toxic Substances and Disease Registry (ATSDR) derives health-based guidance values to estimate daily human exposure to hazardous substances that are likely to be without appreciable risk of adverse noncancer effects for specific routes and durations of exposure. Most of these guidance values are derived from data showing external dose/health effect relationships. However, for chemicals that persist in the body, information on body burdens may provide more accurate understanding of their toxicity. This article evaluates the exposure versus body burden approaches using 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and lead as examples.

Lead and delta-aminolevulinic acid dehydratase polymorphism: where does it lead? A meta-analysis.

BACKGROUND: Lead poisoning affects many organs in the body. Lead inhibits delta-aminolevulinic acid dehydratase (ALAD), an enzyme with two co-dominantly expressed alleles, ALAD1 and ALAD2. OBJECTIVE: Our meta-analysis studied the effects of the ALAD polymorphism on a) blood and bone lead levels and b) indicators of target organ toxicity. DATA SOURCE: We included studies reporting one or more of the following by individuals with genotypes ALAD1-1 and ALAD1-2/2-2: blood lead level (BLL), tibia or trabecular lead level, zinc protoporphyrin (ZPP), hemoglobin, serum creatinine, blood urea nitrogen (BUN), dimercaptosuccinic acid-chelatable lead, or blood pressure. DATA EXTRACTION: Sample sizes, means, and standard deviations were extracted for the genotype groups. DATA SYNTHESIS: There was a statistically significant association between ALAD2 carriers and higher BLL in lead-exposed workers (weighted mean differences of 1.93 microg/dL). There was no association with ALAD carrier status among environmentally exposed adults with BLLs < 10 microg/dL. ALAD2 carriers were potentially protected against adverse hemapoietic effects (ZPP and hemoglobin levels), perhaps because of decreased lead bioavailability to heme pathway enzymes. CONCLUSION: Carriers of the ALAD2 allele had higher BLLs than those who were ALAD1 homozygous and higher hemoglobin and lower ZPP, and the latter seems to be inversely related to BLL. Effects on other organs were not well delineated, partly because of the small number of subjects studied and potential modifications caused by other proteins in target tissues or by other polymorphic genes.