A physiologically based toxicokinetic model of inhalation exposure to xylenes in Caucasian men.

Widespread exposure to the volatile aromatic hydrocarbons, ortho-, meta-, and para-xylene occurs in many industries including the manufacture of plastics, pharmaceuticals, and synthetic fibers. This paper describes the development of a physiologically based toxicokinetic model using biomonitoring data to quantify the kinetics of ortho-, meta-, and para-xylenes. Serial blood concentrations of deuterium-labeled xylene isomers were obtained over 4 days after 37 controlled, 2h inhalation exposures to different concentrations of the isomers. Peak toxicant concentrations in blood occurred in all subjects at the termination of exposure. Systemic clearance averaged 116 L/h+/-34 L/h, 117 L/h+/-23 L/h, and 129 L/h+/-33 L/h for ortho-, para-, and meta-xylene, respectively. The half-life of each toxicant in the terminal phase (>90 h post-exposure) was fit by the model, yielding values of 30.3+/-10.2 h for para-xylene, 33.0+/-11.7 h for meta-xylene and 38.5+/-18.2 h for ortho-xylene. Significant isomeric differences were found (p<0.05) for toxicant half-life, clearance and extrahepatic metabolism. Inter-individual variability seen in this study suggests that airborne concentration guidelines may not protect all workers. A Biological Exposure Index is preferred for this purpose since it is integrative and reflective of inter-individual kinetic variability.

Assessment of PCB congener analytical methods: do they meet risk assessment needs?

Congener-specific PCB analysis allows use of toxic equivalency (TEQ) TCDD-based risk assessment approaches when analytical methods are sufficiently sensitive. Many efforts to analyze fish samples for PCB congeners report the majority of samples as non-detects; these data are of little use for human health risk assessment if the limits of analytical detection exceed levels of potential health concern. However, increasing analytical sensitivity is costly and technically difficult. An approach to assess analytical sensitivity needs for risk assessment by defining toxicological endpoints of concern and acceptable risk levels is presented. This framework was applied to assessment of potential PCB TEQ cancer risks to the general United States population and tribal consumers of Columbia River fish, but may be easily adjusted for other situations. A probabilistic model was used to calculate the necessary analytical sensitivity for PCB TEQ cancer risk assessment using the Environmental Protection Agency's new draft cancer risk slope factor for TCDD and fish consumption data. Desired levels of analytical sensitivity were estimated for the congener expected to contribute the most to PCB TEQ, PCB 126, and compared to limits of detection for various analytical methods. The financial and health value of methods with different levels of analytical sensitivity were compared using a value of information approach, which includes analytical cost and cost of potential health outcomes, and a proposed risk assessment utility approach which considers the relative health protectiveness of analytical options non-monetarily. Sensitivity analyses indicate that average consumption rate, cancer risk slope factor choice, and knowledge of existing PCB contamination are important considerations for planning PCB congener analysis.

Evaluation of media and derivatization chemistry for six aldehydes in a passive sampler.

We evaluated the GMD passive sampler for its suitability to measure six aldehydes over a 7-d period in population exposure studies. The six target aldehydes were formaldehyde, acetaldehyde, acrolein, crotonaldehyde, glyoxal, and methylglyoxal. The GMD sampler contains a silica gel-impregnated cellulose pad coated with 2,4-dinitrophenylhydrazine (DNPH) hydrochloride. This agent reacts with formaldehyde to form a hydrazone that is quantified with a high-performance liquid chromatograph. The GMD sampler was tested for background contamination and aldehyde recoveries after 0, 1, and 7 d of storage. Results indicated that the GMD monitor, as currently manufactured, is suitable for shorter-term sampling (up to 24 h) of formaldehyde and acetaldehyde. It is however not acceptable for sampling of acetaldehyde, acrolein, crotonaldehyde, glyoxal, and methylglyoxal over a 7-d exposure period due to the chemical reactions on the silica gel-impregnated cellulose pad. Glyoxal- and methylglyoxal-DNPH derivatives formed on the cellulose and Teflon-coated glass fiber pads that had been prepared with glycerol under acidic and oxidative conditions. Acrolein- and crotonaldehyde-DNPH derivatives diminish through the reverse reaction of the DNPH derivatives to form free aldehydes under acidic conditions. We showed that the unknown reaction products of acrolein and crotonaldehyde derivatives were not pyrazolines but probably resulted from E/Zisomerization. These conversion reactions are favored in acidic conditions present in either the derivatization solution or the collection medium. The most consistent recovery was obtained on glass fiber pads. In particular, recoveries of crotonaldehyde- and acrolein-DNPH derivatives were increased through the use of a pH 4 buffered derivatization solution. These chemical instability problems were overcome by using a pH 4 buffer (citric acid/sodium citrate) and an alternative hygroscopic agent (1,3-butanediol) in the DNPH derivatization solution. Results with DNPH derivatives from these spiking experiments were further confirmed with gas-phase spiking experiments. We determined the optimal acidity, buffer solution, and concentrations of the buffer solution and 1,3-butanediol for the DNPH derivatization solution. This new formulation of the DNPH derivatization solution can be used for collection of the six target aldehydes over a 7-d sampling period.

Measurement of urinary methoxyphenols and their use for biological monitoring of wood smoke exposure.

A urinary assay for methoxyphenols was developed for the biological monitoring of wood smoke exposure. Methoxyphenols in 10-ml samples of urine were extracted after acid hydrolysis using XAD in a solid-phase extraction cartridge. The methoxyphenols were eluted with ethyl acetate and then analyzed by gas chromatography/mass spectrometry. Specific chemicals quantified were guaiacol, 4-methylguaiacol, 4-ethylguaiacol, 4-propylguaiacol, syringol, 4-methylsyringol, 4-ethylsyringol, vanillin, eugenol, and syringaldehyde. Recoveries ranged from 60 to 90%, with coefficients of variation of < or =20%. Background levels of the compounds were measured in 21 nonsmoking adults. Guaiacol, 4-methylguaiacol, eugenol, and vanillin were detected in all subjects. An experimental feeding of a commercial wood smoke flavoring demonstrated that methoxyphenols were rapidly and efficiently eliminated in urine. Preliminary field studies demonstrated that urinary excretion rates of some methoxyphenols increased after inhalation exposure to wood smoke.

Biologically based pesticide dose estimates for children in an agricultural community.

Current pesticide health risk assessments in the United States require the characterization of aggregate exposure and cumulative risk in the setting of food tolerances. Biologic monitoring can aggregate exposures from all sources and routes, and can integrate exposures for chemicals with a common mechanism of action. Its value was demonstrated in a recent study of organophosphorus (OP) pesticide exposure among 109 children in an agricultural community in Washington State; 91 of the children had parents working in agriculture. We estimated individual OP pesticide doses from urinary metabolite concentrations with a deterministic steady state model, and compared them to toxicologic reference values. We evaluated doses by assuming that metabolites were attributable entirely to either azinphos-methyl or phosmet, the two OP pesticides used most frequently in the region. Creatinine-adjusted average dose estimates during the 6- to 8-week spraying season ranged from 0 to 36 microg/kg/day. For children whose parents worked in agriculture as either orchard applicators or as fieldworkers, 56% of the doses estimated for the spray season exceeded the U.S. Environmental Protection Agency (EPA) chronic dietary reference dose, and 19% exceeded the World Health Organization acceptable daily intake values for azinphos-methyl. The corresponding values for children whose parents did not work in agriculture were 44 and 22%, respectively. The percentage of children exceeding the relevant reference values for phosmet was substantially lower (< 10%). Single-day dose estimates ranged from 0 to 72 microg/kg/day, and 26% of these exceeded the EPA acute reference dose for azinphos-methyl. We also generated dose estimates by adjustment for total daily urine volume, and these estimates were consistently higher than the creatinine-adjusted estimates. None of the dose estimates exceeded the empirically derived no-observable-adverse-effect levels for these compounds. The study took place in an agricultural region during a period of active spraying, so the dose estimates for this population should not be considered representative of exposures in the general population. The findings indicate that children living in agricultural regions represent an important subpopulation for public health evaluation, and that their exposures fall within a range of regulatory concern. They also demonstrate that biologically based exposure measures can provide data for health risk evaluations in such populations.

Improved cleanup and determination of dialkyl phosphates in the urine of children exposed to organophosphorus insecticides.

Analysis of dialkylphosphate urinary metabolites of organophosphorus insecticides has been used to estimate dose in nonoccupationally exposed populations, including children. Analytical methods must continue to be improved in order to accurately and reproducibly measure less than 10 ng/mL of these metabolites. Dialkyl phosphates are commonly determined as their pentafluorobenzyl bromide derivatives via gas chromatography (GC) with flame photometric detection. Presented here is an improved method for precleanup of urine using solid-phase extraction, followed by derivatization and GC analysis. The method includes the quantitative determination of the following dialkyl phosphate metabolites: dimethylphosphate, diethylphosphate, dimethylthiophosphate, diethylthiophosphate, and dimethyldithiophosphate. Additional cleanup of urine samples allows for increasing sample size and improving sensitivity while minimizing interferences and variability associated with derivatization. Sample aliquot size was 5 mL with limits of quantitation of 10 ng/mL of urine for dimethylphosphate and diethylphosphate and 2 ng/mL of urine for dimethylthiophosphate, diethylthiophosphate, and dimethyldithiophosphate. This level of method sensitivity allows for quantitative determination of trace dialkyl phosphates in approximately 75% of individuals in nonoccupationally exposed populations. This streamlined method increases sample throughput, provides a clean extract for analysis, and requires no custom glassware.

A comparison of 1H8- and 2H8-toluene toxicokinetics in men.

1. To examine the bioequivalence of an isotope-labelled tracer to study toxicant disposition, we conducted 33 controlled human exposures to a mixture of 50 ppm 1H8-toluene and 50 ppm 2H8-toluene for 2 h, and measured concentrations in blood and breath, and metabolite levels in urine for 100 h post-exposure. 2. A physiologically based kinetic (PBK) model found that compared with 1H8-toluene, 2H8-toluene had a 6.4+/-13% (mean+/-SD) lower AUC, a 6.5+/-13% higher systemic clearance (1.46+/-0.27 versus 1.38+/-0.25 l/h-kg), a 17+/-22% larger terminal volume of distribution (66.4+/-14 versus 57.2+/-10 l/kg) and a 9.7+/-26% longer terminal half-life (38+/-12 versus 34+/-10 h) (p < 0.05 for all comparisons). 3. The higher 2H8-toluene clearance may have been due to an increased rate of ring oxidation, consistent with the 17% higher observed fraction of 2H5- versus 1H5-cresol metabolites in urine. 4. The larger terminal volume and half-lives for 2H8-toluene suggested a higher adipose tissue/blood partition coefficient. 5. Observed isotope differences were small compared with interindividual differences in 1H8-toluene kinetics from previous studies. 6. The PBK model allowed us to ascribe observed isotope differences in solvent toxicokinetics to underlying physiologic mechanisms.

Reproductive endocrine effects of acute exposure to toluene in men and women.

OBJECTIVES: Despite observation of adverse reproductive effects of toluene, including alterations of serum gonadotropins (luteinising hormone (LH) and follicle stimulating hormone (FSH)) in humans, little is known of the mechanism of toxicity. The hypothesis was tested that toluene acutely suppresses pulsatile gonadotropin secretion by measuring LH and FSH at frequent intervals during controlled exposure to toluene. METHODS: Women in the follicular and luteal phases of the menstrual cycle and men were randomised to inhale filtered air with or without 50 ppm toluene through a mouthpiece for 3 hours (19% of the OSHA permissible exposure limit). Blood was sampled by intravenous catheter at 20 minute intervals for 3 hours before, 3 hours during, and 3 hours after exposure. Plasma LH, FSH, and testosterone were measured. Pulse amplitude, pulse frequency, and mean concentrations of LH and FSH for each of the 3 hour periods before, during and after exposure to toluene versus sham exposure were calculated with the ULTRA pulse detection program and compared by analysis of variance (ANOVA) with repeated measures. RESULTS: In men mean concentrations of LH showed a significant interaction (p < 0.05) between exposure and sampling period, with a greater LH decline during exposure to toluene than sham exposure. However, there was no concomitant effect on testosterone concentrations. The LH pulse frequency of women in the luteal phase showed a trend towards a significant interaction between exposure and sampling period (p = 0.06), with a greater decline in pulse frequency during exposure to toluene than sham exposure. There were no other significant effects of exposure to toluene. CONCLUSIONS: Three hour exposure to 50 ppm toluene did not result in abnormal episodic LH or FSH secretion profiles, however, subtle effects on LH secretion in men and women in the luteal phase were found. The clinical relevance of these effects is unclear, indicating the need for further study of reproductive function in exposed workers.

Individual prior information in a physiological model of 2H8-toluene kinetics: an empirical Bayes estimation strategy.

Physiologically-based toxicokinetic (PBTK) models are widely used to quantify whole-body kinetics of various substances. However, since they attempt to reproduce anatomical structures and physiological events, they have a high number of parameters. Their identification from kinetic data alone is often impossible, and other information about the parameters is needed to render the model identifiable. The most commonly used approach consists of independently measuring, or taking fom literature sources, some of the parameters, fixing them in the kinetic model, and then performing model identification on a reduced number of less certain parameters. This results in a substantial reduction of the degrees of freedom of the model. In this study, we show that this method results in final estimates of the free parameters whose precision is overestimated. We then compared this approach with an empirical Bayes approach, which takes into account not only the mean value, but also the error associated with the independently determined parameters. Blood and breath 2H8-toluene washout curves, obtained in 17 subjects, were analyzed with a previously presented PBTK model suitable for person-specific dosimetry. Model parameters with the greatest effect on predicted levels were alveolar ventilation rate QPC, fat tissue fraction VFC, blood-air partition coefficient Kb, fraction of cardiac output to fat Qa/co and rate of extrahepatic metabolism Vmax-p. Differences in the measured and Bayesian-fitted values of QPC, VFC and Kb were significant (p < 0.05), and the precision of the fitted values Vmax-p and Qa/co went from 11 +/- 5% to 75 +/- 170% (NS) and from 8 +/- 2% to 9 +/- 2% (p < 0.05) respectively. The empirical Bayes approach did not result in less reliable parameter estimates: rather, it pointed out that the precision of parameter estimates can be overly optimistic when other parameters in the model, either directly measured or taken from literature sources, are treated as known without error. In conclusion, an empirical Bayes approach to parameter estimation resulted in a better model fit, different final parameter estimates, and more realistic parameter precisions.

Biological monitoring of controlled toluene exposure.

OBJECTIVES: Widespread exposure to toluene occurs in the printing, painting, automotive, shoemaking, and speaker-manufacturing industries. The relationship between air concentrations and the absorbed dose is confounded by dermal exposure, personal protective devices, movement throughout the workplace, and interindividual differences in toluene uptake and elimination. METHODS: To determine the best biological indicator of exposure we examined the blood and alveolar breath concentrations of toluene as well as the urinary excretion rates of hippuric acid and of o-, m-, and p-cresols from 33 controlled human inhalation exposures to 50 ppm for 2 h. RESULTS: Among the metabolites, o-cresol was least influenced by background contributions, whereas the p-cresol and hippuric acid rates were obscured by endogenous and dietary sources. Toluene levels in alveolar breath proved to be the most accurate and noninvasive indicator of the absorbed dose. A physiologic model described blood and breath data using four measured anthropometric parameters and the fit values of extrahepatic metabolism and adipose-tissue blood flow. CONCLUSIONS: After breathing rate and extrahepatic metabolism had been set to conservative (protective) values (the 97.5th and 2.5th percentiles, respectively) the model predicted that pre-final-shift breath levels of < or =10 micromol/m3 and post-final-shift levels of < or =150 micromol/m3 corresponded to average workplace exposure levels of < or =50 ppm toluene. Alternately, we used the distributions and covariances of the measured and fit model parameters to yield conservative pre-final-shift levels of < or =7.3 micromol/m3 and post-final-shift breath levels of < or =120 micromol/m3 that were reflective of workplace exposure levels of < or =50 ppm toluene.

Relationship of urinary arsenic to intake estimates and a biomarker of effect, bladder cell micronuclei.

The purpose of this study was to investigate methods for ascertaining arsenic exposure for use in biomarker studies. Urinary arsenic concentration is considered a good measure of recent arsenic exposure and is commonly used to monitor exposure in environmental and occupational settings. However, measurements reflect exposure only in the last few days. To cover longer time periods exposure can be estimated using arsenic intake data, calculated by combining measures of environmental arsenic and inhalation/ingestion rates. We compared these different exposure assessment approaches in a population chronically exposed to arsenic in drinking water in northern Chile. The study group consisted of 232 people, some drinking water low in arsenic (15 micrograms/l) and others drinking water with high arsenic concentrations (up to 670 micrograms/l). First morning urine samples and questionnaire data, including fluid intake information, were collected from all participants. Exfoliated bladder cells were collected from male participants for the bladder cell micronuclei assay. Eight different indices of exposure were generated, six based on urinary arsenic (microgram As/l urine; microgram As/g creatinine; microgram InAs/l urine; microgram MMA/l urine; microgram DMA/l urine; microgram As/h, excreted), and two on fluid intake data (microgram As/day, ingested; microgram As/l fluid ingested-day). The relationship between the different exposure indices was explored using correlation analysis. In men, exposure indices were also related to a biomarker of effect, bladder cell micronuclei. While creatinine-adjusted urinary arsenic concentrations had the strongest correlations with the two intake estimates (r = 0.76, r = 0.81), unadjusted urinary arsenic showed the strongest relationship with bladder cell micronuclei. These data suggest that, in the case of the bladder, unadjusted urinary arsenic concentrations better reflect the effective target organ dose compared to other exposure measures for biomarker studies.

Simulated dermal contamination with capillary samples and field cholinesterase biomonitoring.

The extensive international use of organophosphorus compounds (OP) results in numerous acute intoxications each year. OPs inhibit acetylcholinesterase, the enzyme responsible for breaking down the neurotransmitter acetylcholine. The World Health Organization recognizes cholinesterase (ChE) biomonitoring as a preventive measure against OP overexposure. The aim of this study was to determine if dermal OP contamination could interfere with current field ChE biomonitoring assays, which use a fingerstick blood sample. In this study we also sought to determine if high levels of a plasma enzyme, A-esterase, could protect ChE from inhibition by hydrolyzing environmentally generated oxons potentially present in a fingerstick sample. A heparinized venous blood sample was collected from a volunteer. Erythrocyte acetylcholinesterase (AChE) and plasma butyrylcholinesterase (PChE) activities were measured using a field-based colorimetric cholinesterase kit. ChE dose-response curves were constructed by allowing 10-microliters blood samples to contact environmentally realistic levels of OP thioate and oxon for 10 s. An inhibition threshold could not be established for PChE when exposed to oxon within the time necessary to perform a fingerstick analysis. AChE was also inhibited by trace amounts of oxon consistent with previously reported environmental levels. These findings suggest that the reliability of field-based biomonitoring results is limited if OP residues remain on a skin surface at the time of sample collection. A-esterase's role in protecting ChE activity was investigated using capillary and venous blood from 30 unexposed individuals. Baseline ChE activities were measured, as were individual A-esterase activities using paraoxon, diazoxon, and phenylacetate as substrates. Results were then compared to ChE activities measured after 10 s of contact with an environmentally realistic amount of OP, containing 1% oxon. Both ChE activities were significantly inhibited, with capillary values being significantly more inhibited than their venous counterparts. However, no protective effect could be associated between the degree of A-esterase activity and the subsequent level of ChE inhibition observed in an individual's blood. These results suggest that (1) if there is any uncertainty about OP skin contamination, venous blood would be a more appropriate specimen to employ when using field ChE biomonitoring kits--it is collected in larger volumes and has essentially no direct contact to dermal surfaces; and (2) A-esterase activity demonstrates no protective effect against ChE inhibition upon a blood droplet's brief contact with an OP residue containing traces of oxon.

Micronuclei in exfoliated bladder cells among individuals chronically exposed to arsenic in drinking water.

Inorganic arsenic is an established cause of lung and skin cancer. Epidemiological evidence from Taiwan suggests that arsenic causes more fatal internal cancers, with the highest relative risks reported for bladder cancer. We conducted a cross-sectional biomarker study in a Chilean male population chronically exposed to high (70 subjects) and low (55 subjects) arsenic levels in their drinking water (average concentrations, 600 and 15 micrograms As/liter, respectively). A fluorescent version of the exfoliated bladder cell micronucleus (MN) assay was used employing fluorescence in situ hybridization with a centromeric probe to identify the presence (MN+) or absence (MN-) of whole chromosomes within micronuclei, thereby determining the mechanism of arsenic-induced genotoxicity in vivo. We divided the study population into quintiles by urinary arsenic levels and found an exposure-dependent increase in micronucleated cell prevalence in quintiles 2-4 (urinary arsenic, 54-729 micrograms/liter). The largest increase appeared when quintile 4 was compared to quintile 1 [prevalence ratio, 3.0; 95% confidence interval (CI), 1.9-4.6]. The prevalence of MN+ increased to 3.1-fold in quintile 4 (95% CI, 1.4-6.6), and the prevalence of MN-increased to 7.5-fold in quintile 3 (95% CI, 2.8-20.3), suggesting that chromosome breakage was the major cause of MN formation. Prevalences of total MN, MN+, and MN- returned to baseline levels in quintile 5 (urinary arsenic, 729-1894 micrograms/liter), perhaps due to cytostasis or cytotoxicity. These results add additional weight to the hypothesis that ingesting arsenic-contaminated water enhances bladder cancer risk and suggest that arsenic induces genetic damage to bladder cells at drinking water levels close to the current United States Maximum Contaminant Level of 50 micrograms/liter for arsenic.

Decrease in bladder cell micronucleus prevalence after intervention to lower the concentration of arsenic in drinking water.

Epidemiological studies performed in Taiwan, Argentina, and Chile suggest that ingestion of arsenic (As) may cause bladder cancer. Because of these findings, we previously investigated the relationship between As ingestion and genetic damage to the urothelium in two cross-sectional biomarker studies, one in Nevada and one in Chile. In both studies, we found that increased levels of micronucleated cells (MNCs) in exfoliated bladder cells were associated with elevated concentrations of As in drinking water, suggesting that As induces genetic damage to bladder cells. To further investigate this relationship, we conducted an intervention study in a subset of highly exposed men (n = 34) from the cross-sectional study in Chile. Subjects whose usual source of water contained about 600 micrograms/liter As were supplied with water lower in As (45 micrograms/liter) for 8 weeks, allowing ample opportunity for renewal and exfoliation of bladder epithelial cells. Mean urinary As levels decreased during the intervention from 742 to 225 micrograms/liter. Bladder MNC prevalence also decreased from 2.63 MNCs/1000 cells preintervention to 1.79 MNCs/1000 cells postintervention (P < 0.05). When the analysis was limited to individuals previously having subcytotoxic urinary As levels (< 700 micrograms/liter), the change between pre- and postintervention MNC was more pronounced: the level decreased from 3.54 to 1.47 MNCs/1000 cells, respectively (P = 0.002). Among smokers, MNC prevalences decreased from 4.45 MNCs/1000 cells preintervention to 1.44 MNCs/1000 cells postintervention (P = 0.002). Among nonsmokers, the decrease was much smaller: 2.04 MNCs/1000 cells preintervention to 1.90 MNCs/1000 cells postintervention (P = 0.25), suggesting that smoker's bladder cells could be more susceptible to genotoxic damage caused by As. The reduction in bladder MNC prevalence with reduction in As intake provides further evidence that As is genotoxic to bladder cells.

Quantitation of o-, m- and p-cresol and deuterated analogs in human urine by gas chromatography with electron capture detection.

A gas chromatographic method for the analysis of cresol metabolites of toluene and [2H8]toluene in urine was developed. Cresol glucuronides and sulfates in urine were hydrolyzed with beta-glucuronidase and arylsulfatase. Following extraction with tert.-butyl methyl ether and solvent exchange into benzene, the cresols were derivatized with heptafluorobutyric anhydride to form the heptafluorobutyrate esters. The derivatives were analyzed by gas chromatography with electron capture detection. Chromatographic resolution was achieved between all cresol isomers and their 2H7 analogs. Calibration ranged from 0.001 to 500 microg/ml. Recoveries were 55-97% and showed no trend with respect to analyte concentration. Within-day precision of analyses of benchmark urine samples had a coefficient of variation of less than 4%. The assay sensitivity was limited by chromatographic background but was sufficient for quantification of the unlabeled cresols in urine from men with only environmental exposure to toluene. Average levels in urine samples from 45 men were 0.023, 0.054 and 37 microg/ml for o-, m- and p-cresol, respectively.

Arsenic methylation patterns before and after changing from high to lower concentrations of arsenic in drinking water.

Inorganic arsenic (In-As), an occupational and environmental human carcinogen, undergoes biomethylation to monomethylarsonate (MMA) and dimethylarsinate (DMA). It has been proposed that saturation of methylation capacity at high exposure levels may lead to a threshold for the carcinogenicity of In-As. The relative distribution of urinary In-As, MMA, and DMA is used as a measure of human methylation capacity. The most common pathway for elevated environmental exposure to In-As worldwide is through drinking water. We conducted a biomarker study in northern Chile of a population chronically exposed to water naturally contaminated with high arsenic content (600 micrograms/l). In this paper we present the results of a prospective follow-up of 73 exposed individuals, who were provided with water of lower arsenic content (45 micrograms/l) for 2 months. The proportions of In-As, MMA, and DMA in urine were compared before and after intervention, and the effect of other factors on the distribution of arsenic metabolites was also analyzed. The findings of this study indicate that the decrease in arsenic exposure was associated with a small decrease in the percent In-As in urine (from 17.8% to 14.6%) and in the MMA/DMA ratio (from 0.23 to 0.18). Other factors such as smoking, gender, age, years of residence, and ethnicity were associated mainly with changes in the MMA/DMA ratio, with smoking having the strongest effect. Nevertheless, the factors investigated accounted for only about 20% of the large interindividual variability observed. Genetic polymorphisms in As-methylating enzymes and other co-factors are likely to contribute to some of the unexplained variation. The changes observed in the percent In-As and in the MMA/DMA ratio do not support an exposure-based threshold for arsenic methylation in humans.

Interindividual differences in 2H8-toluene toxicokinetics assessed by semiempirical physiologically based model.

Recent applications of physiologically band toxicokinetic (PBTK) models have used animal to human scaling, the hypothetical average man, and Monte Carlo techniques to estimate human exposure to toxicants. Our study built a PBTK model suitable for person-specific dosimetry. Individual measurements of age, ventilation rate, blood/air partition coefficient, body weight, and adipose tissue fraction were made on 26 male subjects exposed to 50 ppm 2H8-toluene and 50 ppm toluene for 2 hr at rest, with collection of venous blood samples for 120 hr postexposure. Fitted lung metabolism was a novel feature of the PBTK model, used to explain a systemic clearance of 2H8-toluene well in excess of hepatic blood flow. A 10-fold interindividual range in venous concentrations was found. Subject-specific modeling explained 91% of the observed data variability, compared to 53% using literature values for model parameters. Body weight, adipose tissue fraction, and blood/air partition coefficient were correlated with terminal half-life, steady-state volume of distribution, and terminal volume of distribution. Lung metabolism was correlated with systemic clearance and terminal half-life. Interindividual differences in lung metabolism resulted in divergent predicted fractions of 2H8-toluene in the body at 2 and 100 hr. An increased adipose fraction led to lower blood concentrations up to 8 hr postexposure, and simulations showed that at 98 hr, adipose tissue contained 97-99% of 2H8-toluene in the body. Use of subject-specific model parameters greatly improved model fit and demonstrated interindividual differences in toxicokinetics.

Methylation study of a population environmentally exposed to arsenic in drinking water.

Methylation is considered the detoxification pathway for inorganic arsenic (InAs), an established human carcinogen. Urinary speciation analysis is used to assess the distribution of metabolites [monomethylarsonate (MMA), dimethylarsinate (DMA), and unmethylated arsenic (InAs)], as indicators of methylation capacity. We conducted a large biomarker study in northern Chile of a population chronically exposed to high levels of arsenic in drinking water. We report the results of the methylation study, which focused on the effects of exposure and other variables on the percent InAs, MMA, DMA, and the ratio of MMA to DMA in urine. The study consisted of 122 people in a town with arsenic water levels around 600 micrograms/l and 98 participants in a neighboring town with arsenic levels in water of about 15 micrograms/l. The corresponding mean urinary arsenic levels were 580 micrograms/l and 60 micrograms/l, of which 18.4% and 14.9% were InAs, respectively. The main differences were found for MMA:DMA; exposure, smoking, and being male were associated with higher MMA:DMA, while longer residence, Atacameño ethnicity, and being female were associated with lower MMA:DMA. Together, these variables explained about 30% of the variability in MMA:DMA. Overall, there was no evidence of a threshold for methylation capacity, even at very high exposures, and the interindividual differences were within a much wider range than those attributed to the variables investigated. The differences in percent InAs were small and within the ranges of other studies of background exposure levels. The biological significance of MMA:DMA, which was more than 1.5 times greater in the exposed group, and its relationship to sex, length of exposure, and ethnicity need further investigation because its relevance to health risk is not clear.

Partition coefficients between human blood or adipose tissue and air for aromatic solvents.

OBJECTIVES: The partitioning of lipophilic toxicants into blood and into adipose tissue plays an important role in the physiological distribution and toxicology of these substances. The partition coefficients between blood and air and adipose tissue and air were determined for widely used aromatic solvents in an in vitro test system using human tissue samples. METHODS: Samples of whole venous blood (N = 35) were drawn from 10 subjects. In addition, samples of perirenal and epididymal adipose tissue were obtained from F344 rats, along with subcutaneous, omental, or inguinal adipose tissue from 43 patients who had undergone surgery. Portions of each tissue were injected into vials for equilibration with atmospheres containing deuterated and nondeuterated organic solvents. Gas chromatographic headspace analysis was then used to determine the partition coefficients between blood and air and adipose tissue and air. RESULTS: The mean partition coefficients between human blood and air or adipose tissue and air were 334 (SE 11) (adipose tissue) for benzene; 1764 (SE 49) (adipose tissue) for ethylbenzene; 3184 (SE 84) (adipose tissue) for styrene; 18.3 (SE 0.24) (blood) and 962 (SE 32) (adipose tissue) for toluene; 35.2 (SE 0.45) (blood) and 2460 (SE 63) (adipose tissue) for O-xylene; 31.9 (SE 0.45) (blood) and 1919 (SE 53) (adipose tissue) for m-xylene; and 39.0 (SE 0.70) (blood) and 2019 (SE 102) for p-xylene. Regression analyses revealed coefficients of determination of 0.88 (human) and 0.98 (rat) between blood and air and log tissue and air. A value of 0.98 was found for partition coefficients between rat and human adipose tissue. CONCLUSIONS: The partition coefficients between blood and air and adipose tissue and air were strongly correlated. The partitioning of aromatic solvents into rat adipose tissue is predictive of partitioning into human adipose tissue.

Pesticides in household dust and soil: exposure pathways for children of agricultural families.

Child of agriculture families are likely to be exposed to agricultural chemicals, even if they are not involved in farm activities. This study was designed to determine whether such children are exposed to higher levels of pesticides than children whose parents are not involved in agriculture and whose homes are not close to farms. Household dust and soil samples were collected in children's play areas from 59 residences in eastern Washington State (26 farming, 22 farmworker, and 11 nonfarming families). The majority of the farm families lived within 200 feet of an operating apple or pear orchard, whereas all reference homes were located at least a quarter of a mile from an orchard. Four organophosphorous (OP) insecticides commonly used on tree fruit were targeted for analysis: azinphosmethyl, chlorpyrifos, parathion, and phosmet. Samples were extracted and analyzed by gas chromatography/mass selective detection. Pesticide concentrations in household dust were significantly higher than in soil for all groups. OP levels for farmer/farm-worker families ranged from nondetectable to 930 ng/g in soil (0.93 ppm) and from nondetectable to 17,000 ng/g in dust (17 ppm); all four OP compounds were found in 62% of household dust samples, and two-thirds of the farm homes contained at least one OP above 1000 ng/g. Residues were found less frequently in reference homes and all levels were below 1000 ng/g. Household dust concentrations for all four target compounds were significantly lower in reference homes when compared to farmer/farmworker homes (Mann Whitney, U test; p < 0.05). These results demonstrate that children of agricultural families have a higher potential for exposure to OP pesticides than children of nonfarm families in this region. Measurable residues of a toxicity, I compound registered exclusively for agricultural use, azcnphosmettyl were found in household dust samples from all study homes, suggesting that low level exposure to such chemicals occurs throughout the region. Children's total and cumulative exposure to this pesticide class from household dust, soil, and other sources warrants further investigation.