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Trimethylbenzenes (Interagency Science Discussion Draft)

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Data/Software
Data/ Software

Results of the BMD analyses for 1,2,4-TMB, 1,2,3-TMB, and 1,3,5-TMB

Author: U.S. EPA (2016) HERO ID: 3103169

[Less] : This zipfile contains all input files (.dax files), analysis files (.opt, .ssn, .(d), and .002 files), . . . [More] : This zipfile contains all input files (.dax files), analysis files (.opt, .ssn, .(d), and .002 files), and output files (.out, .emf, and .plt files) used in and generated by the BMD analyses on endpoints considered for the derivation of reference values for 1,2,4-TMB, 123, and 1,3,5-TMB in the Interagency Science Discussion draft of the Toxicological Review for Trimethylbenzenes. This zipfile also contains all BMDS Wizard files (macro enabled Excel workbooks, .xlsm) that were used in the BMD modeling analyses. These BMDS Wizard files store within them all the modeling results for an individual endpoint, and can be used to interpret these endpoint-specific results holistically, rather than inspecting model-specific .out and .plt files. Lastly, this zipfile contains a modeling report (.docx) for each modeling analysis; these reports were used to create the BMD Modeling appendix (Appendix D) in the Supplemental Information Document for Trimethylbenzenes.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Hemimellitene (1,2,3-trimethylbenzene) in the liver, lung, kidney, and blood, and dimethylbenzoic acid isomers in the liver, lung, kidney and urine of rats after single and repeated inhalation exposure to hemimellitene

Authors: Świercz, R; Majcherek, W; Wąsowicz, W (2016) International Journal of Occupational Medicine and Environmental Health 29:113-128. HERO ID: 3044616

[Less] OBJECTIVES: The aim of the study has been to explore hemimellitene distribution in blood, liver, lung . . . [More] OBJECTIVES: The aim of the study has been to explore hemimellitene distribution in blood, liver, lung and kidney as well as toxicokinetics of its elimination from blood of rats after single and repeated inhalation exposure to this compound. Tissue distribution and excretion with urine of 2-dimethylbenzoic acids (2,3-DMBA and 2,6-DMBA) were also evaluated.

MATERIAL AND METHODS: Male outbred IMP:WIST rats were used in the experiment. The animals were exposed to hemimellitene vapors at the nominal concentration of 25 ppm, 100 ppm, and 250 ppm in the dynamic inhalation chambers for 6 h for single exposure purpose and for 4 weeks (6 h/day for 5 day/week) for repeated exposure purposes.

RESULTS: Significantly lower concentrations of hemimellitene were detected in the blood and tissues of animals after repeated inhalation exposure of animals to hemimellitene vapors, which points to reduced retention of the chemical in the lungs of the experimental rats. The trend of hemimellitene elimination from the blood depended solely on exposure intensity, irrespective of exposure time, both after single and repeated exposure. As regards the 2 determined hemimellitene metabolites, the major trend of the metabolic transformation involved formation of 2,3-DMBA.

CONCLUSIONS: The significantly higher urinary 2,3-DMBA concentration after repeated exposure shows that hemimellitene induces enzymatic processes in the rat.

Data/Software
Data/ Software

PBPK data files for TMB (updated February 2016)

Author: U.S. EPA (2016) [Data files]. Research Triangle Park, NC: U.S. Environmental Protection Agency. [PBPK] HERO ID: 3103168

[Less] This model code package contains the PBPK files used in the testing and validation of the PBPK model . . . [More] This model code package contains the PBPK files used in the testing and validation of the PBPK model used in the Toxicological Review for Trimethylbenzenes, as well the files used in the PBPK extrapolations of inhalation data for the purpose of deriving reference concentrations, and the route-to-route extrapolation of inhalation data to oral exposures for the purpose of deriving reference doses.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

New look at BTEX: Are ambient levels a problem?

Authors: Bolden, AL; Kwiatkowski, CF; Colborn, T (2015) Environmental Science and Technology 49:5261-5276. [Review] HERO ID: 2857163

[Less] Benzene, toluene, ethylbenzene, and xylene (BTEX) are retrieved during fossil fuel extraction and used . . . [More] Benzene, toluene, ethylbenzene, and xylene (BTEX) are retrieved during fossil fuel extraction and used as solvents in consumer and industrial products, as gasoline additives, and as intermediates in the synthesis of organic compounds for many consumer products. Emissions from the combustion of gasoline and diesel fuels are the largest contributors to atmospheric BTEX concentrations. However, levels indoors (where people spend greater than 83% of their time) can be many times greater than outdoors. In this review we identified epidemiological studies assessing the noncancer health impacts of ambient level BTEX exposure (i.e., nonoccupational) and discussed how the health conditions may be hormonally mediated. Health effects significantly associated with ambient level exposure included sperm abnormalities, reduced fetal growth, cardiovascular disease, respiratory dysfunction, asthma, sensitization to common antigens, and more. Several hormones including estrogens, androgens, glucocorticoids, insulin, and serotonin may be involved in these health outcomes. This analysis suggests that all four chemicals may have endocrine disrupting properties at exposure levels below reference concentrations (i.e., safe levels) issued by the U.S. Environmental Protection Agency. These data should be considered when evaluating the use of BTEX in consumer and industrial products and indicates a need to change how chemicals present at low concentrations are assessed and regulated.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

The sub-chronic toxicity of regular White Spirit in rats

Authors: Carrillo, J-C; Adenuga, MD; Mckee, RH (2014) Regulatory Toxicology and Pharmacology 70:222-230. HERO ID: 2897466

[Less] Hydrocarbon solvents are mostly complex substances (UVCB) with carbon numbers in the range of approximately . . . [More] Hydrocarbon solvents are mostly complex substances (UVCB) with carbon numbers in the range of approximately C5-C20. One of the most common types is a C9-C14 aliphatic solvent containing approximately 20% aromatics and commonly known as White Spirit in Europe and mineral spirits in the US. In previous repeated inhalation toxicity studies, White Spirit was reported to cause minimal systemic effects in most animal species with few effects other than male rat-specific kidney changes at levels up to approximately 2000mg/m(3). In the present study male and female rats were exposed to White Spirit vapors, 6h/day, 5days/week for 13weeks at levels of approximately 2000, 4000, or 8000mg/m(3) to assess the potential for effects at higher exposure levels. All of the rats survived the treatment period. In life observations were largely restricted to acute central nervous system (CNS) effects in the high exposure group. Terminal body weights of high exposure groups animals were significantly below control values. Statistically significant differences in the clinical and hematological observations were small and within normal physiological limits. Weights of some organs including liver, spleen and kidneys were elevated, but microscopic examination indicated that the only pathological effects were changes in the kidneys of the male rats, consistent with an α2u-globulin-mediated process, which is gender and species-specific and not relevant to humans. The overall no observed adverse effect level (NOAEC) was 4000mg/m(3).

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Neurobehavioral performance in volunteers after inhalation of white spirits with high and low aromatic content

Authors: Juran, SA; Johanson, G; Ernstgård, L; Iregren, A; van Thriel, C (2014) Archives of Toxicology 88:1127-1140. HERO ID: 3044623

[Less] The content of aromatic hydrocarbons in solvent mixtures, such as white spirits (WS), has been assumed . . . [More] The content of aromatic hydrocarbons in solvent mixtures, such as white spirits (WS), has been assumed a major contributor to the neurotoxic effects of these compounds. Hence, dearomatized WS have been introduced to the market rapidly in the last decade. Studies investigating other aromatic hydrocarbons (toluene) and animal models have supported the aforementioned assumption, but the current study is the first one to compare acute neurobehavioral effects of exposure to aromatic and dearomatized WS (aWS, daWS) content in human volunteers at current occupational exposure limit values. In a pseudo-randomized crossover design, six female and six male healthy volunteers were exposed to aWS and daWS at two concentrations (100 and 300 mg/m(3)) and to clean air for 4 h at rest. During each of the five exposure conditions, volunteers performed five neurobehavioral tasks that were selected following a multidisciplinary approach that accounted for findings from the cognitive neurosciences and mechanisms of solvent toxicity. Two of the tasks indicated performance changes during aromatic WS exposure, the working memory (WM) and the response shifting task, but both effects are difficult to interpret due to low mean accuracy in the WM task and due to a lack of dose-response relationship in the response shifting task. Healthy human volunteers showed weak and inconsistent neurobehavioral impairment after 4-h exposures to 100 and 300 mg/m(3) aromatic or dearomatized WS. Our multidisciplinary approach of selecting neurobehavioral test methods may guide the test selection strategies in future studies.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

The sub-chronic oral toxicity of 1,3,5-trimethylbenzene in Sprague-Dawley rats

Authors: Adenuga, D; Carrillo, JC; Mckee, RH (2014) Regulatory Toxicology and Pharmacology 69:143-153. HERO ID: 2899217

[Less] The systemic toxicity of a trimethylbenzene isomer and constituent of C9 aromatic solvents (1,3,5-trimethylbenzene, . . . [More] The systemic toxicity of a trimethylbenzene isomer and constituent of C9 aromatic solvents (1,3,5-trimethylbenzene, 135-TMB) was studied in Sprague-Dawley rats following a 90-day oral gavage exposure to 0, 50, 200 and 600 mg/kg/day. No statistically significant effects on body weight, body weight gain or food consumption were observed at study termination. Treatment-related changes in clinical chemistry parameters at the end of the 90-day dosing period were limited to small, but statistically significant, increases in phosphorus levels in high dose males and females. Liver enlargement in high dose male/female rats was considered an adaptive response as this was reversible and was not associated with histopathological lesions or increased liver enzyme markers indicative of liver damage. Kidney weight changes were limited to a small, but statistically significant, increase in relative weights in high dose males. This was not associated with histopathological lesions and thus not considered toxicologically relevant. Overall, the No-Observed-Adverse-Effect-Level (NOAEL) was the highest concentration tested (600 mg/kg/day). The results of the present study are relevant for assessing the risk of trimethylbenzenes through the oral route of exposure and provide a basis for the development of provisional screening values for trimethylbenzene isomers while avoiding the uncertainty associated with route-to-route extrapolation.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Hydrocarbon toxicity: A review

Authors: Tormoehlen, LM; Tekulve, KJ; Nañagas, KA (2014) Clinical Toxicology 52:479-489. [Review] HERO ID: 3068427

[Less] CONTEXT: Clinical effects of hydrocarbon exposure have been reported since 1897. These . . . [More] CONTEXT: Clinical effects of hydrocarbon exposure have been reported since 1897. These substances are ubiquitous, and their exposures are common. The specific hydrocarbon and route of exposure will determine the clinical effect, and an understanding of this is helpful in the care of the hydrocarbon-exposed patient.

OBJECTIVE: To complete a comprehensive review of the literature on hydrocarbon toxicity and summarize the findings.

METHODS: Relevant literature was identified through searches of Medline (PubMed/OVID) and Cochrane Library databases (inclusive of years 1975-2013), as well as from multiple toxicology textbooks. Bibliographies of the identified articles were also reviewed. Search terms included combinations of the following: hydrocarbons, inhalants, encephalopathy, coma, cognitive deficits, inhalant abuse, huffing, sudden sniffing death, toluene, renal tubular acidosis, metabolic acidosis, arrhythmia, dermatitis, and aspiration pneumonitis. All pertinent clinical trials, observational studies, and case reports relevant to hydrocarbon exposure and published in English were reviewed. Chronic, occupational hydrocarbon toxicity was not included.

RESULTS: Exposure to hydrocarbons occurs through one of the following routes: inhalation, ingestion with or without aspiration, or dermal exposure. Inhalational abuse is associated with central nervous system depression, metabolic acidosis, and arrhythmia. The exact mechanism of the CNS depression is unknown, but experimental evidence suggests effects on NMDA, dopamine, and GABA receptors. Chronic toluene inhalation causes a non-anion gap metabolic acidosis associated with hypokalemia. Halogenated hydrocarbon abuse can cause a fatal malignant arrhythmia, termed "sudden sniffing death". Individuals who regularly abuse hydrocarbons are more likely to be polysubstance users, exhibit criminal or violent behavior, and develop memory and other cognitive deficits. Heavy, long-term use results in cerebellar dysfunction, encephalopathy, weakness, and dementia. Neuroimaging may demonstrate leukoencephalopathy in these cases. Acute exposures improve with cessation of exposure. Electrolyte and fluid replacement will improve metabolic acidosis. Arrhythmias are precipitated via catecholamine surge, and beta blockers are presumed protective. Aspiration of hydrocarbons causes a potentially fatal pneumonitis. Symptoms may include cough, wheezing respiratory distress, and hypoxia. Bilateral interstitial infiltrates may be delayed for several hours after the development of pneumonitis. Treatment consists of supportive care, supplemental oxygen, and may require intubation and admission to an intensive care unit in severe cases. Unfortunately, aspiration pneumonitis remains a leading cause of poisoning mortality in children. Dermal exposure can cause dermatitis, chemical burns, and defatting injury. Oral exposure can cause local irritation as well as vomiting, diarrhea, and abdominal pain.

CONCLUSION: Acute hydrocarbon exposure can result in a wide array of pathology, such as encephalopathy, pneumonitis, arrhythmia, acidosis, and dermatitis. Intentional inhalational and accidental ingestion exposures with aspiration lead to the greatest morbidity and mortality.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Ototoxicity effects of low exposure to solvent mixture among paint manufacturing workers

Authors: Juárez-Pérez, CA; Torres-Valenzuela, A; Haro-García, LC; Borja-Aburto, VH; Aguilar-Madrid, G (2014) International Journal of Audiology 53:370-376. HERO ID: 3063457

[Less] OBJECTIVE: To evaluate auditory function in a group of workers exposed to organic solvent . . . [More] OBJECTIVE: To evaluate auditory function in a group of workers exposed to organic solvent mixture at a paint factory.

DESIGN: Cross-sectional study.

STUDY SAMPLE: One hundred and sixty-one workers were studied, 77 exposed to solvents and 84 unexposed. Fourteen solvents were measured, including toluene, xylene, and n-hexane. Pure-tone audiometry and brainstem auditory-evoked potentials (BAEP) were performed. Industrial noise was < 85 dBA and exposure levels to organic solvents were low.

RESULTS: The exposed group showed a hearing impairment in both ears compared with the unexposed workers. Multiple linear regression models adjusted by age, chronic pathologies, and environmental noise for frequency means between 125 and 8000 Hz produced the following results: for the left ear, R(2) = 33.3%, exposed vs. unexposed β = 4.1 (p < 0.001); and for the right ear, R(2) = 38%, exposed vs. unexposed β = 4.8 (p < 0.001). Adjusted for age and chronic pathologies, waves III and V, and interpeak interval latencies were increased (p < 0.05) in both ears in the exposed group.

CONCLUSIONS: Although solvent mixture concentrations and noise levels were low, our results demonstrate that there may be a concurrent ototoxicity and neurotoxicity condition and emphasize the importance of including BAEP analysis for comprehensive assessments. Future studies that include otoacoustic emissions assessments to monitor cochlear function and central auditory processing tests are imperative.

The "refereed" or "peer review" status of a journal comes from the Ulrichsweb Global Serials Directory (http://ulrichsweb.serialssolutions.com/), as supplied by the publisher. The term refers to the system of critical evaluation of manuscripts/articles by professional colleagues or peers. The content of refereed publications is sanctioned, vetted, or otherwise approved by a peer-review or editorial board. The peer-review and evaluation system is utilized to protect, maintain, and raise the quality of scholarly material published in serials. Publications subject to the referee process are assumed, then, to contain higher quality content than those that are not.
Peer Reviewed Journal Article

Developmental and reproductive effects of chemicals associated with unconventional oil and natural gas operations

Authors: Webb, E; Bushkin-Bedient, S; Cheng, A; Kassotis, CD; Balise, V; Nagel, SC (2014) Reviews on Environmental Health 29:307-318. [Review] HERO ID: 2773367

[Less] Unconventional oil and gas (UOG) operations have the potential to increase air and water pollution in . . . [More] Unconventional oil and gas (UOG) operations have the potential to increase air and water pollution in communities located near UOG operations. Every stage of UOG operation from well construction to extraction, operations, transportation, and distribution can lead to air and water contamination. Hundreds of chemicals are associated with the process of unconventional oil and natural gas production. In this work, we review the scientific literature providing evidence that adult and early life exposure to chemicals associated with UOG operations can result in adverse reproductive health and developmental effects in humans. Volatile organic compounds (VOCs) [including benzene, toluene, ethyl benzene, and xylene (BTEX) and formaldehyde] and heavy metals (including arsenic, cadmium and lead) are just a few of the known contributors to reduced air and water quality that pose a threat to human developmental and reproductive health. The developing fetus is particularly sensitive to environmental factors, which include air and water pollution. Research shows that there are critical windows of vulnerability during prenatal and early postnatal development, during which chemical exposures can cause potentially permanent damage to the growing embryo and fetus. Many of the air and water pollutants found near UOG operation sites are recognized as being developmental and reproductive toxicants; therefore there is a compelling need to increase our knowledge of the potential health consequences for adults, infants, and children from these chemicals through rapid and thorough health research investigation.