Evaluation of NHANES biomonitoring data for volatile organic chemicals in blood: application of chemical-specific screening criteria.

Available biomonitoring data for volatile organic chemicals (VOCs) in blood from the National Health and Nutrition Examination Survey (NHANES) (2003-2004) (CDC, 2009) were compared with recently derived screening biomonitoring equivalent (BE) values (Aylward et al., 2010). A BE is defined as the estimated concentration or range of concentrations of a chemical or its metabolites in a biological medium (blood, urine, or other medium) that is consistent with an existing health-based exposure guidance value. Blood concentrations of VOCs from the NHANES data set were compared with predicted screening BE values based upon a hazard quotient (HQ) for individual chemicals, and a hazard index (HI) approach for combined exposures. HI values for detected chemicals were generally at or below a value of 1, suggesting that the potential for deleterious effects is low. However, smoking was an important determinant of HI and HQ values. Detected levels of benzene in non-smokers were within the range of BE values corresponding to a 1 × 10(-6)-1 × 10(-4) range for upper-bound cancer risk; in smokers, levels of benzene were at the upper end of or exceeded this range. For VOCs that were not detected in the NHANES sampling, analytical detection limits were generally sufficiently sensitive to detect concentrations consistent with existing non-cancer and cancer risk-based exposure guidance values. Interpretations of measured blood concentrations of VOCs must be made with caution due to the substantial within-individual, within-day fluctuations in levels expected due to the rapid elimination of VOCs.

The effects of perchlorate on thyroidal gene expression are different from the effects of iodide deficiency.

Perchlorate (ClO4⁻), which is a ubiquitous and persistent ion, competitively interferes with iodide (I) accumulation in the thyroid, producing I deficiency (ID), which may result in reduced thyroid hormone synthesis and secretion. Human studies suggest that ClO4⁻ presents little risk in healthy individuals; however, the precautionary principle demands that the sensitive populations of ID adults and mothers require extra consideration. In an attempt to determine whether the effects on gene expression were similar, the thyroidal effects of ClO4⁻ (10 mg/kg) treatment for 14 d in drinking water were compared with those produced by 8 wk of ID in rats. The thyroids were collected (n = 3 each group) and total mRNA was analyzed using the Affymetrix Rat Genome 230 2.0 GeneChip. Changes in gene expression were compared with appropriate control groups. The twofold gene changes due to ID were compared with alterations due to ClO4⁻ treatment. One hundred and eighty-nine transcripts were changed by the ID diet and 722 transcripts were altered by the ClO4⁻ treatment. Thirty-four percent of the transcripts changed by the I-deficient diet were also altered by ClO4⁻ and generally in the same direction. Three specific transporter genes, AQP1, NIS, and SLC22A3, were changed by both treatments, indicating that the membrane-specific changes were similar. Iodide deficiency primarily produced alterations in retinol and calcium signaling pathways and ClO4⁻ primarily produced changes related to the accumulation of extracellular matrix proteins. This study provides evidence that ClO4⁻, at least at this dose level, changes more genes and alters different genes compared to ID.

Chemical-specific screening criteria for interpretation of biomonitoring data for volatile organic compounds (VOCs)--application of steady-state PBPK model solutions.

The National Health and Nutrition Examination Survey (NHANES) generates population-representative biomonitoring data for many chemicals including volatile organic compounds (VOCs) in blood. However, no health or risk-based screening values are available to evaluate these data from a health safety perspective or to use in prioritizing among chemicals for possible risk management actions. We gathered existing risk assessment-based chronic exposure reference values such as reference doses (RfDs), reference concentrations (RfCs), tolerable daily intakes (TDIs), cancer slope factors, etc. and key pharmacokinetic model parameters for 47 VOCs. Using steady-state solutions to a generic physiologically-based pharmacokinetic (PBPK) model structure, we estimated chemical-specific steady-state venous blood concentrations across chemicals associated with unit oral and inhalation exposure rates and with chronic exposure at the identified exposure reference values. The geometric means of the slopes relating modeled steady-state blood concentrations to steady-state exposure to a unit oral dose or unit inhalation concentration among 38 compounds with available pharmacokinetic parameters were 12.0 microg/L per mg/kg-d (geometric standard deviation [GSD] of 3.2) and 3.2 microg/L per mg/m(3) (GSD=1.7), respectively. Chemical-specific blood concentration screening values based on non-cancer reference values for both oral and inhalation exposure range from 0.0005 to 100 microg/L; blood concentrations associated with cancer risk-specific doses at the 1E-05 risk level ranged from 5E-06 to 6E-02 microg/L. The distribution of modeled steady-state blood concentrations associated with unit exposure levels across VOCs may provide a basis for estimating blood concentration screening values for VOCs that lack chemical-specific pharmacokinetic data. The screening blood concentrations presented here provide a tool for risk assessment-based evaluation of population biomonitoring data for VOCs and are most appropriately applied to central tendency estimates for such datasets.

Disinfection by-product formation and mitigation strategies in point-of-use chlorination with sodium dichloroisocyanurate in Tanzania.

Almost a billion persons lack access to improved drinking water, and diarrheal diseases cause an estimated 1.87 million deaths per year. Sodium dichloroisocyanurate (NaDCC) tablets are widely recommended for household water treatment to reduce diarrhea. Because NaDCC is directly added to untreated water sources, concerns have been raised about the potential health impact of disinfection by-products. This study investigated trihalomethane (THM) production in water from six sources used for drinking (0.6-888.5 nephelometric turbidity units) near Arusha, Tanzania. No sample collected at 1, 8, and 24 hours after NaDCC addition exceeded the World Health Organization guideline values for either individual or total THMs. Ceramic filtration, sand filtration, cloth filtration, and settling and decanting were not effective mitigation strategies to reduce THM formation. Chlorine residual and THM formation were not significantly different in NaDCC and sodium hypochlorite treatment. Household chlorination of turbid and non-turbid waters did not create THM concentrations that exceeded health risk guidelines.

Long-term environmental exposure to perchlorate through drinking water and thyroid function during pregnancy and the neonatal period.

We have conducted a longitudinal epidemiologic study among pregnant women from three cities in northern Chile: Taltal with 114 microg/L, Chañaral with 6 microg/L, and Antofagasta with 0.5 microg/L perchlorate in the public drinking water. We tested the hypothesis that long-term exposure to perchlorate at these levels may cause a situation analogous to iodine deficiency, thus causing increases in thyrotropin (TSH) and thyroglobulin (Tg) levels and decreased levels of free thyroxine (FT4), in either the mother during the early stages of gestation or the neonate at birth, or in the fetus cause growth retardation. We found no increases in Tg or TSH and no decreases in FT4 among either the women during early pregnancy (16.1 +/- 4.1 weeks), late pregnancy (32.4 +/- 3.0 weeks), or the neonates at birth related to perchlorate in drinking water. Neonatal birth weight, length, and head circumference were not different among the three cities and were consistent with current U.S. norms. Therefore, perchlorate in drinking water at 114 microg/L did not cause changes in neonatal thyroid function or fetal growth retardation. Median urinary iodine among the entire cohort was 269 microg/L, intermediate between that of pregnant women in the United States at National Health and Nutrition Examination Survey (NHANES) I and at NHANES III and consistent with current World Health Organization (WHO) recommendations. Median breast milk iodine was not decreased in the cities with detectable perchlorate. Analysis of maternal urinary perchlorate excretion indicates an additional dietary source of perchlorate.

5-Chlorouracil, a marker of DNA damage from hypochlorous acid during inflammation. A gas chromatography-mass spectrometry assay.

Hypochlorous acid (HOCl), generated from H2O2 and Cl- by myeloperoxidase in activated neutrophils, causes tissue damage during inflammation. We have developed a simple, sensitive (approximately 0.2 fmol on column) and specific GC-MS assay for the detection of 5-chlorouracil (5-ClUra), a signature product of HOCl-mediated damage to nucleobases. In this assay, 5-ClUra is released from isolated DNA by a digestion with nuclease P1, alkaline phosphatase, and thymidine phosphorylase (TP), or from chlorinated nucleosides in biological fluids by TP. The freed 5-ClUra is derivatized with 3, 5-bis-(trifluoromethyl)-benzyl bromide, which is detected by negative chemical ionization mass spectrometry. The assay can be used to simultaneously detect other halogenated uracils including bromouracil. Using this assay, we showed that 5-ClUra is generated by the reaction of low micromolar HOCl with (deoxy)cytidine, (deoxy)uridine, and DNA. In cell cultures, an increase of 5-ClUra was detected in DNA when cells were treated with sublethal doses of HOCl and allowed to proliferate. The elevation of 5-ClUra was markedly accentuated when physiologically relevant concentrations of (deoxy)uridine, (deoxy) cytidine, uracil, or cytosine were present in the medium during HOCl treatment. In the carrageenan-induced inflammation model in rats, chlorinated nucleosides was significantly increased, compared with controls, in the exudate fluid isolated from the inflammation site. Our study provides the direct evidence that chlorinated nucleosides are found in the inflammation site and can be incorporated in DNA during cell/tissue proliferation. These findings may be relevant to the carcinogenesis associated with chronic inflammation.