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Use of physiologically based pharmacokinetic modeling to support development of an acute (24-hour) health-based inhalation guideline for manganese.
Perry, CS, Blanchette, AD, Vivanco, SN, Verwiel, AH, Proctor, DM
Regulatory toxicology and pharmacology : RTP. 2023;:105518
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Abstract
The toxicokinetics of manganese (Mn) are controlled through homeostasis because Mn is an essential element. However, at elevated doses, Mn is also neurotoxic and has been associated with respiratory, reproductive, and developmental effects. While health-based criteria have been developed for chronic inhalation exposure to ambient Mn, guidelines for short-term (24-h) environmental exposure are also needed. We reviewed US state, federal, and international health-based inhalation toxicity criteria, and conducted a literature search of recent publications. The studies deemed most appropriate to derive a 24-h guideline have a LOAEL of 1500 μg/m3 for inflammatory airway changes and biochemical measures of oxidative stress in the brain following 90 total hours of exposure in monkeys. We applied a cumulative uncertainty factor of 300 to this point of departure, resulting in a 24-h guideline of 5 μg/m3. To address uncertainty regarding potential neurotoxicity, we used a previously published physiologically based pharmacokinetic model for Mn to predict levels of Mn in the brain target tissue (i.e., globus pallidus) for exposure at 5 μg/m3 for two short-term human exposure scenarios. The PBPK model predictions support a short-term guideline of 5 μg/m3 as protective of both respiratory effects and neurotoxicity, including exposures of infants and children.
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A spatial gradient of bacterial diversity in the human oral cavity shaped by salivary flow.
Proctor, DM, Fukuyama, JA, Loomer, PM, Armitage, GC, Lee, SA, Davis, NM, Ryder, MI, Holmes, SP, Relman, DA
Nature communications. 2018;9(1):681
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Plain language summary
Identifying spatial patterns in the human microbiota is necessary to provide insight into mechanisms that either maintain or disrupt its healthy state. The aim of this study was to identify the type and extent of oral spatial patterns formed by bacterial communities, as well as observe the impact of low salivary flow on the spatial patterns. Dental exams were performed on 31 participants to evaluate the oral health status and follow-up was dependent on group allocation. This study found bacterial communities were distinguishable depending on types of teeth and tissue. Further, bacteria on soft and hard tissues varied across the front and back of the oral cavity in a gradient-manner, implying that salivary flow plays a role in establishing the bacterial community gradient in the oral cavity. Based on these results, the authors recommend spatial patterns and processes be explored in other body parts to better understand health and disease.
Abstract
Spatial and temporal patterns in microbial communities provide insights into the forces that shape them, their functions and roles in health and disease. Here, we used spatial and ecological statistics to analyze the role that saliva plays in structuring bacterial communities of the human mouth using >9000 dental and mucosal samples. We show that regardless of tissue type (teeth, alveolar mucosa, keratinized gingiva, or buccal mucosa), surface-associated bacterial communities vary along an ecological gradient from the front to the back of the mouth, and that on exposed tooth surfaces, the gradient is pronounced on lingual compared to buccal surfaces. Furthermore, our data suggest that this gradient is attenuated in individuals with low salivary flow due to Sjögren's syndrome. Taken together, our findings imply that salivary flow influences the spatial organization of microbial communities and that biogeographical patterns may be useful for understanding host physiological processes and for predicting disease.
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The effects of perchlorate, nitrate, and thiocyanate on free thyroxine for potentially sensitive subpopulations of the 2001-2002 and 2007-2008 National Health and Nutrition Examination Surveys.
Suh, M, Abraham, L, Hixon, JG, Proctor, DM
Journal of exposure science & environmental epidemiology. 2014;(6):579-87
Abstract
Among women with urinary iodine concentration <100 μg/l in the 2001-2002 National Health and Nutrition Examination Survey (NHANES), urinary perchlorate was associated with significant changes in thyroid stimulating hormone and total thyroxine (T4). Although perchlorate, nitrate, and thiocyanate all potentially act to inhibit iodide uptake, free T4 was not found to be associated with exposure to these chemicals in the same data. Fetuses of pregnant mothers with iodine deficiency are thought to be a sensitive subpopulation for perchlorate exposure, but the potential associations between free T4 and exposure to these chemicals among pregnant mothers in NHANES 2001-2002 and 2007-2008 have not been specifically evaluated to date. This study investigates the potential associations between urinary perchlorate, nitrate, and thiocyanate and serum free T4 in individuals with low urinary iodine levels and pregnant women. Multivariate regression models of free T4 were conducted and included urinary perchlorate, nitrate, thiocyanate, and covariates known to have an impact on the thyroid (anti-thyroid peroxidase (TPO) antibodies, age, race/ethnicity, body mass index, and hours of fasting). Meta-analyses were also conducted on non-pregnant and on pregnant women from the two survey cycles. Urinary nitrate was associated with serum free T4 in non-pregnant women of NHANES 2001-2002 who had urinary iodine ≥100 μg/l. In the meta-analysis, urinary perchlorate, nitrate, and thiocyanate were significant predictors of serum free T4 in non-pregnant women. No association was found in men and pregnant women. TPO antibodies were significant predictors of free T4 among non-pregnant women only when the models included urinary perchlorate, nitrate, or thiocyanate. Risk assessment for perchlorate exposure should consider co-exposure to nitrate and thiocyanate.
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Occupational exposure to hexavalent chromium and cancers of the gastrointestinal tract: a meta-analysis.
Gatto, NM, Kelsh, MA, Mai, DH, Suh, M, Proctor, DM
Cancer epidemiology. 2010;(4):388-99
Abstract
INTRODUCTION We conducted a systematic literature review and meta-analysis of oral cavity, esophageal, stomach, small intestine, colon, and rectal cancers among workers occupationally exposed to Cr(VI). METHODS Using PubMed, studies published from 1950 to 2009 evaluating the relationship between Cr(VI) exposure and GI cancers were identified. Measures of effect and variability were extracted from 32 studies meeting specific inclusion criteria, and meta-analysis summary relative risk measures were calculated using random effects models and inverse variance weighting methods. RESULTS Meta-standardized mortality ratios (SMRs) were, for cancer of the: oral cavity [1.02 (95% CI=0.77-1.34)]; esophagus [1.17 (95% CI=0.90-1.51)]; stomach [1.09 (95% CI=0.93-1.28)]; colon [0.89 (95% CI=0.70-1.12)]; and rectum [1.17 (95% CI=0.98-1.39)]. Analyses of more highly exposed subgroups included in the studies or subgroups based on geographic region or by industry with recognized Cr(VI) exposures (welding, chrome plating, chromate production, and pigment production) did not result in elevated meta-SMRs except for esophageal cancer among US cohorts [meta-SMR=1.49 (95% CI=1.06-2.09)]. However, that finding was based on a subgroup of only four studies, one of which was a PMR study. Potential confounding by socioeconomic status (SES), diet and/or smoking, or limitations due to the healthy-worker effect (HWE) were evaluated, and while smoking, diet and SES may be important factors that may have upwardly biased the meta-SMRs, HWE is not likely to have significantly affected the summary results. None of three studies reporting small intestine cancers observed a statistically significant increased risk. DISCUSSION These meta-analyses and literature review indicate that Cr(VI)-exposed workers are not at a greater risk of GI cancers than the general population.