Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
Records 1-11 (of 11 Records) |
Query Trace: Mumtaz MM[original query] |
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Worker studies suggest unique liver carcinogenicity potential of polyvinyl chloride microplastics
Zarus GM , Muianga C , Brenner S , Stallings K , Casillas G , Pohl HR , Mumtaz MM , Gehle K . Am J Ind Med 2023 66 (12) 1033-1047 BACKGROUND: Plastic debris pervades our environment. Some breaks down into microplastics (MPs) that can enter and distribute in living organisms causing effects in multiple target organs. MPs have been demonstrated to harm animals through environmental exposure. Laboratory animal studies are still insufficient to evaluate human impact. And while MPs have been found in human tissues, the health effects at environmental exposure levels are unclear. AIM: We reviewed and summarized existing evidence on health effects from occupational exposure to MPs. Additionally, the diverse effects documented for workers were organized by MP type and associated co-contaminants. Evidence of the unique effects of polyvinyl chloride (PVC) on liver was then highlighted. METHODS: We conducted two stepwise online literature reviews of publications focused on the health risks associated with occupational MP exposures. This information was supplemented with findings from animal studies. RESULTS: Our analysis focused on 34 published studies on occupational health effects from MP exposure with half involving exposure to PVC and the other half a variety of other MPs to compare. Liver effects following PVC exposure were reported for workers. While PVC exposure causes liver toxicity and increases the risk of liver cancers, including angiosarcomas and hepatocellular carcinomas, the carcinogenic effects of work-related exposure to other MPs, such as polystyrene and polyethylene, are not well understood. CONCLUSION: The data supporting liver toxicity are strongest for PVC exposure. Overall, the evidence of liver toxicity from occupational exposure to MPs other than PVC is lacking. The PVC worker data summarized here can be useful in assisting clinicians evaluating exposure histories from PVC exposure and designing future cell, animal, and population exposure-effect research studies. |
Advances in Assessing Hazard and Risk to Emerging Threats and Emergency Response: Comparing and Contrasting Efforts of Three Federal Agencies
Mumtaz MM , Nickle RA , Lambert JC , Johnson MS . Toxicol Sci 2021 185 (1) 1-9 Federal statutes authorize several agencies to protect human populations from chemical emergencies and provide guidance to evacuate, clean, and re-occupy affected areas. Each of the authorized federal agencies have developed programs to provide managers, public health officials, and regulators, with a rapid assessment of potential hazards and risks associated with chemical emergencies. Emergency responses vary based on exposure scenarios, routes, temporal considerations, and the substance(s) present. Traditional chemical assessments and derivation of toxicity values are time-intensive, typically requiring large amounts of human epidemiological and experimental animal data. When a rapid assessment of health effects is needed, an integrated computational approach of augmenting extant toxicity data with in vitro (new alternative toxicity testing methods) data can provide a quick, evidence-based solution. In so doing, multiple streams of data can be used, including literature searches, hazard, dose-response, physicochemical, and environmental fate and transport property data, in vitro cell bioactivity testing and toxicogenomics. The field of toxicology is moving, ever so slowly, towards increased use of this approach as it transforms from observational to predictive science. The challenge is to objectively and transparently derive toxicity values using this approach to protect human health and the environment. Presented here are examples and efforts toward rapid risk assessment that demonstrate unified, parallel, and complementary work to provide timely protection in times of chemical emergency. |
Per- and polyfluoroalkyl mixtures toxicity assessment "Proof-of-Concept" illustration for the hazard index approach
Mumtaz MM , Buser MC , Pohl HR . J Toxicol Environ Health A 2021 84 (13) 1-15 The 2018 ATSDR mixture framework recommends three approaches including the hazard index (HI) for environmental mixture toxicity assessment. Per- and polyfluoroalkyls (PFAS) are found in our environment and general populations. Recent experimental mixture toxicity studies of perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) and an assessment of 17 PFAS indicate the use of additivity for their joint toxicity assessment. The aim of this investigation was to detail the stepwise procedures and examine the extent and use of the HI approach for PFAS mixture assessment. Using estimated general public lifetime exposures (high, medium, and low), binary mixtures of PFOS and PFOA yielded, respectively, hazard indices (HIs) of 30.67, 8.33, and 3.63 for developmental toxicity; 10.67, 5.04, and 2.34 for immunological toxicity; 3.57, 1.68, and 0.78 for endocrine toxicity; 4.51, 1.73, and 0.79 for hepatic toxicity; and 15.08, 2.29, and 0.88 for reproductive toxicity. A heterogeneous mixture of PFOA, PFAS, dioxin (CDD), and polybrominated compounds (PBDE) for high exposure scenario yielded HIs of 30.99 for developmental, 10.77 for immunological, 3.64 for endocrine, 4.61 for hepatic, and 17.36 for reproductive effects. The HI values are used as a screening tool; the potential concern for exposures rises as HI values increase. For HI values >1, a follow-up including further analysis of specific exposures, use of internal dosimetry, and uncertainty factors is conducted before recommending appropriate actions. The HI approach appears suitable to address present-day PFAS public health concerns for initial assessment of multiple health effects, until further insights are gained into their mechanistic toxicology.The findings and conclusions in this article are those of the author(s) and do not necessarily represent the official position of the Centers for Disease Control and Prevention/the Agency for Toxic Substances and Disease Registry. |
Prevalence and associated demographic characteristics of exposure to multiple metals and their species in human populations: The United States NHANES, 2007-2012
Shim YK , Lewin MD , Ruiz P , Eichner JE , Mumtaz MM . J Toxicol Environ Health A 2017 80 (9) 1-11 Lead (Pb), cadmium (Cd), mercury (Hg), and arsenic (As) are among the top 10 pollutants of global health concern. Studies have shown that exposures to these metals produce severe adverse effects. However, the mechanisms underlying these effects, particularly joint toxicities, are poorly understood in humans. The objective of this investigation was to identify and characterize prevalent combinations of these metals and their species in the U.S. NHANES population to provide background data for future studies of potential metal interactions. Exposure was defined as urine or blood levels ≥ medians of the NHANES 2007-2012 participants ≥6 years (n = 7408). Adjusted-odds ratios (adj-OR) and 95% confidence intervals were determined for covariates (age, gender, and race/ethnicity, cotinine and body mass index). Species-specific analysis was also conducted for As and Hg including iAs (urinary arsenous acid and/or arsenic acid), met-iAs (urinary monomethylarsonic acid and/or dimethylarsinic acid), and oHg (blood methyl-mercury and/or ethyl-mercury). For combinations of As and Hg species, age- and gender-specific prevalence was determined among NHANES 2011-2012 participants (n = 2342). Data showed that approximately 49.3% of the population contained a combination of three or more metals. The most prevalent unique specific combinations were Pb/Cd/Hg/As, Pb/Cd/Hg, and Pb/Cd. Age was consistently associated with these combinations: adj-ORs ranged from 10.9 (Pb/Cd) to 11.2 (Pb/Cd/Hg/As). Race/ethnicity was significant for Pb/Cd/Hg/As. Among women of reproductive age, frequency of oHg/iAs/met-iAS and oHg/met-iAs was 22.9 and 40.3%, respectively. These findings may help prioritize efforts to assess joint toxicities and their impact on public health. |
Carcinogenic air toxics exposure and their cancer-related health impacts in the United States
Zhou Y , Li C , Huijbregts MA , Mumtaz MM . PLoS One 2015 10 (10) e0140013 Public health protection from air pollution can be achieved more effectively by shifting from a single-pollutant approach to a multi-pollutant approach. To develop such multi-pollutant approaches, identifying which air pollutants are present most frequently is essential. This study aims to determine the frequently found carcinogenic air toxics or hazardous air pollutants (HAPs) combinations across the United States as well as to analyze the health impacts of developing cancer due to exposure to these HAPs. To identify the most commonly found carcinogenic air toxics combinations, we first identified HAPs with cancer risk greater than one in a million in more than 5% of the census tracts across the United States, based on the National-Scale Air Toxics Assessment (NATA) by the U.S. EPA for year 2005. We then calculated the frequencies of their two-component (binary), and three-component (ternary) combinations. To quantify the cancer-related health impacts, we focused on the 10 most frequently found HAPs with national average cancer risk greater than one in a million. Their cancer-related health impacts were calculated by converting lifetime cancer risk reported in NATA 2005 to years of healthy life lost or Disability-Adjusted Life Years (DALYs). We found that the most frequently found air toxics with cancer risk greater than one in a million are formaldehyde, carbon tetrachloride, acetaldehyde, and benzene. The most frequently occurring binary pairs and ternary mixtures are the various combinations of these four air toxics. Analysis of urban and rural HAPs did not reveal significant differences in the top combinations of these chemicals. The cumulative annual cancer-related health impacts of inhaling the top 10 carcinogenic air toxics included was about 1,600 DALYs in the United States or 0.6 DALYs per 100,000 people. Formaldehyde and benzene together contribute nearly 60 percent of the total cancer-related health impacts. Our study shows that although there are many carcinogenic air toxics, only a few of them affect public health significantly at the national level in the United States, based on the frequency of occurrence of air toxics mixtures and cancer-related public health impacts. Future research is needed on their joint toxicity and cumulative health impacts. |
Assessment of hydroxylated metabolites of polychlorinated biphenyls as potential xenoestrogens: a QSAR comparative analysis
Ruiz P , Myshkin E , Quigley P , Faroon O , Wheeler JS , Mumtaz MM , Brennan RJ . SAR QSAR Environ Res 2013 24 (5) 393-416 Alternative methods, including quantitative structure-activity relationships (QSAR), are being used increasingly when appropriate data for toxicity evaluation of chemicals are not available. Approximately 40 mono-hydroxylated polychlorinated biphenyls (OH-PCBs) have been identified in humans. They represent a health and environmental concern because some of them have been shown to have agonist or antagonist interactions with human hormone receptors. This could lead to modulation of steroid hormone receptor pathways and endocrine system disruption. We performed QSAR analyses using available estrogenic activity (human estrogen receptor ER alpha) data for 71 OH-PCBs. The modelling was performed using multiple molecular descriptors including electronic, molecular, constitutional, topological, and geometrical endpoints. Multiple linear regressions and recursive partitioning were used to best fit descriptors. The results show that the position of the hydroxyl substitution, polarizability, and meta adjacent un-substituted carbon pairs at the phenolic ring contribute towards greater estrogenic activity for these chemicals. These comparative QSAR models may be used for predictive toxicity, and identification of health consequences of PCB metabolites that lack empirical data. Such information will help prioritize such molecules for additional testing, guide future basic laboratory research studies, and help the health/risk assessment community understand the complex nature of chemical mixtures. |
Interspecies uncertainty in molecular responses and toxicity of mixtures
Mumtaz MM , Pohl HR . Exp Suppl 2012 101 361-79 Most of the experimental toxicity testing data for chemicals are generated through the use of laboratory animals, namely, rodents such as rats and mice or other species. Interspecies extrapolation is needed to nullify the differences between species so as to use such data for human health/risk assessment. Thus, understanding of interspecies differences is important in extrapolating the laboratory results to humans and conducting human risk assessments based on current credible scientific knowledge. Major causes of interspecies differences in anatomy and physiology, toxicokinetics, injury repair, molecular receptors, and signal transduction pathways responsible for variations in responses to toxic chemicals are outlined. In the risk assessment process, uncertainty associated with data gaps in our knowledge is reflected by application of uncertainty factors for interspecies differences. Refinement of the risk assessment methods is the ultimate goal as we strive to realistically evaluate the impact of toxic chemicals on human populations. Using specific examples from current risk assessment practice, this chapter illustrates the integration of interspecies differences in evaluation of individual chemicals and chemical mixtures. |
Joint toxicity of alkoxyethanol mixtures: contribution of in silico applications.
Pohl HR , Ruiz P , Scinicariello F , Mumtaz MM . Regul Toxicol Pharmacol 2012 64 (1) 134-42 Exposure to chemicals occurs often as mixtures. Presented in this paper is information on alkoxyethanols and the impact they might have on human health in combination with some commonly found aliphatic and aromatic compounds. Our studies to evaluate the joint toxicity of these chemicals among themselves and in combination with other chemicals reveal a variety of possible outcomes depending on the exposure scenario. The interactions are predominantly based on metabolic pathways and are common among several solvents and organic compounds. Quantitative structure activity relationship (QSAR) analysis can be used with high confidence to identify chemicals that will interact to influence overall joint toxicity. Potential human exposure to a combination of alkoxyethanol, toluene and substituted benzenes may increase reproductive and developmental disease conditions. Inheritable gene alterations result in changes in the enzyme function in different subpopulations causing variations in quantity and/or quality of particular isoenzymes. These changes are responsible for differential metabolism of chemicals in species, genders, and life stages and are often the basis of a population's susceptibility. Unique genotypes introduced as a function of migration can alter the genetic makeup of any given population. Hence special consideration should be given to susceptible populations while conducting chemical health risk assessments. |
Translational research to develop a human PBPK models tool kit - volatile organic compounds (VOCs)
Mumtaz MM , Ray M , Crowell SR , Keys D , Fisher J , Ruiz P . J Toxicol Environ Health A 2012 75 (1) 6-24 Toxicity and exposure evaluations remain the two of the key components of human health assessment. While improvement in exposure assessment relies on a better understanding of human behavior patterns, toxicity assessment still relies to a great extent on animal toxicity testing and human epidemiological studies. Recent advances in computer modeling of the dose-response relationship and distribution of xenobiotics in humans to important target tissues have advanced our abilities to assess toxicity. In particular, physiologically based pharmacokinetic (PBPK) models are among the tools than can enhance toxicity assessment accuracy. Many PBPK models are available to the health assessor, but most are so difficult to use that health assessors rarely use them. To encourage their use these models need to have transparent and user-friendly formats. To this end the Agency for Toxic Substances and Disease Registry (ATSDR) is using translational research to increase PBPK model accessibility, understandability, and use in the site-specific health assessment arena. The agency has initiated development of a human PBPK tool-kit for certain high priority pollutants. The tool kit comprises a series of suitable models. The models are recoded in a single computer simulation language and evaluated for use by health assessors. While not necessarily being state-of-the-art code for each chemical, the models will be sufficiently accurate to use for screening purposes. This article presents a generic, seven-compartment PBPK model for six priority volatile organic compounds (VOCs): benzene (BEN), carbon tetrachloride (CCl(4)), dichloromethane (DCM), perchloroethylene (PCE), trichloroethylene (TCE), and vinyl chloride (VC). Limited comparisons of the generic and original model predictions to published kinetic data were conducted. A goodness of fit was determined by calculating the means of the sum of the squared differences (MSSDs) for simulation vs. experimental kinetic data using the generic and original models. Using simplified solvent exposure assumptions for oral ingestion and inhalation, steady-state blood concentrations of each solvent were simulated for exposures equivalent to the ATSDR Minimal Risk Levels (MRLs). The predicted blood levels were then compared to those reported in the National Health and Nutrition ExaminationSurvey (NHANES). With the notable exception of BEN, simulations of combined oral and inhalation MRLs using our generic VOC model yielded blood concentrations well above those reported for the 95th percentile blood concentrations for the U.S. populations, suggesting no health concerns. When the PBPK tool kit is fully developed, risk assessors will have a readily accessible tool for evaluating human exposure to a variety of environmental pollutants. |
Mixtures and their risk assessment in toxicology
Mumtaz MM , Hansen H , Pohl HR . Met Ions Life Sci 2011 8 61-80 For communities generally and for persons living in the vicinity of waste sites specifically, potential exposures to chemical mixtures are genuine concerns. Such concerns often arise from perceptions of a site's higher than anticipated toxicity due to synergistic interactions among chemicals. This chapter outlines some historical approaches to mixtures risk assessment. It also outlines ATSDR's current approach to toxicity risk assessment. The ATSDR's joint toxicity assessment guidance for chemical mixtures addresses interactions among components of chemical mixtures. The guidance recommends a series of steps that include simple calculations for a systematic analysis of data leading to conclusions regarding any hazards chemical mixtures might pose. These conclusions can, in turn, lead to recommendations such as targeted research to fill data gaps, development of new methods using current science, and health education to raise awareness of residents and health care providers. The chapter also provides examples of future trends in chemical mixtures assessment. |
Binary weight-of-evidence evaluations of chemical interactions--15 years of experience
Pohl HR , Mumtaz MM , Scinicariello F , Hansen H . Regul Toxicol Pharmacol 2009 54 (3) 264-71 The paper reflects on the last 15years of experience in the field of mixtures risk assessment. It summarizes results found in various documents developed by the Agency for Toxic Substances and Disease Registry (ATSDR) of the weight-of-evidence (WOE) approach applied to 380 binary combinations of chemicals. Of these evaluations, 156 assessments indicated possible additivity of effects [=], 76 indicated synergism (greater-than-additive effects [>]), and 57 indicated antagonism (less-than-additive effects [<]). However, 91 combinations lacked the minimum information needed for making any assessments and, hence, were undetermined. The paper provides examples of the rationale behind some of the WOE decisions and discusses the importance of expert judgments in risk assessment evaluations. Examples are given regarding the importance of human variability in mixtures' ability to affect human health and regarding the dose versus effect relationships. |
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