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D A Kalman

Publications and source records attributed to D A Kalman.

At least 19 recordsLinked to original sources
PubMed1999

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.

Adult↗
PubMed1998

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.

Adult↗
PubMed1997

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.

Administration, Inhalation↗
PubMed1997

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.

Adolescent↗
PubMed1997

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.

Acetylcholinesterase↗
PubMed1997

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.

Adult↗
PubMed1997

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.

Adult↗
PubMed1996

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.

Absorption↗
PubMed1996

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.

Adult↗
PubMed1996

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.

Adolescent↗
PubMed1996

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.

Adipose Tissue↗
PubMed1995

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.

Adult↗
PubMed1993

Evaluation of stable isotope-labeled probes in the study of solvent pharmacokinetics in human subjects.

The relationship between biomarkers of exposure (such as concentrations of toxicants in blood or breath, or metabolites in urine) and toxicant dose for individuals is influenced by many person- and episode-specific factors which contribute to overall variability in biomarker level for a given dose. This variability results in imprecise biological marker-based estimates of dose for individuals. We hypothesize that pharmacokinetic data from stable-isotope (deuterated) analogs can be used with a pharmacokinetic model to account for individual-related sources of variation, leading to more precise methods of dose estimation for individuals. To establish the degree of similarity in the pharmacokinetics of unlabeled (d0-) and fully deuterated (D8-) toluene, 21 men (ages 20-45) inhaled an equal molar mixture for 2h. Washout kinetics for both compounds were followed for 4 d in alveolar air and blood. Both compounds exhibited three-phase elimination kinetics in both fluids. The third phase was not always definable for d0-toluene because of concurrent uncontrolled environmental exposures. Considering data from only the first two phases, concentrations of d0- and d8-toluene in alveolar air and blood were well correlated for all subjects, even though pharmacokinetic parameters varied among individuals by 5-9 folds. Further experiments are needed to discern whether correlations between d0- and d8-toluene for the third phase are influenced by an isotope effect; present data support use of d8-toluene as a suitable probe for d0-kinetics.

Adult↗
PubMed1991

Capillary gas chromatographic method for mandelic and phenylglyoxylic acids in urine.

In support of an occupational investigation of styrene exposure, a capillary gas chromatographic method was developed for the quantitation of the styrene metabolites mandelic and phenylglyoxylic acids. The method was based on that of Guillemin and Bauer, in which phenylglyoxylic acid was converted to mandelic acid by reduction before instrumental analysis. The earlier method had to be modified for use with capillary columns; the resulting method was sensitive, selective and reproducible. The detection limit was approximately 0.001 mg/ml urine. Approximately less than 5% relative precision was achieved in the range of 0.05-2 mg/ml urine. Mandelic acid was resolved from other components of urine and from by-products of derivatization.

Air Pollutants, Occupational↗
PubMed1990

Pathways of human exposure to arsenic in a community surrounding a copper smelter.

Several studies have found elevated levels of urinary arsenic among residents living near a copper smelter in Tacoma, Washington. To assess pathways of exposure to arsenic from the smelter, biological and environmental samples were collected longitudinally from 121 households up to 8 miles from the smelter. The concentration of inorganic and methylated arsenic compounds in spot urine samples was used as the primary measure of exposure to environmental arsenic. Urinary concentration of arsenic dropped off to a constant background level within one-half mile of the smelter in contrast to environmental concentrations, which decreased more steadily with increasing distance. Among all age-sex-specific groups in all areas, only children ages 0-6 living within one-half mile of the smelter had elevated levels of arsenic in urine. A separate analysis of data for these children suggests that hand-to-mouth activity was the primary source of exposure. Inhalation of ambient air and resuspension of contaminated soil were not important sources of exposure for children or adults.

Adolescent↗
PubMed1990

The effect of variable environmental arsenic contamination on urinary concentrations of arsenic species.

Urinary arsenic species have been determined for approximately 3000 urine samples obtained from residents of a community surrounding an arsenic-emitting copper smelter. Levels of inorganic, monomethylated and dimethylated arsenic species ranged from less than 1 microgram/L (the instrumental detection limit) to 180 micrograms/L seen for dimethyl arsenic. Comparison of a subsample of this population that had the least environmental contamination with the subsample having highest environmental arsenic concentrations showed small but statistically significant differences in urinary arsenic levels for all species except dimethylated arsenic. However, for children under 7 years of age living in areas with increased environmental arsenic contamination, there was a larger and equally significant (p less than 0.001) increase in all urinary species. This effect was more pronounced in males (5-fold increase in median sum of species concentration over control group) than in females (2-fold increase in median sum of species concentration over control group) and was observed as a weaker effect in the next higher age group (7-13 years of age). Reported consumption of seafood also was significantly related to increased urinary dimethyl arsenic, but changes in distribution among the urinary arsenic species detected was not a sensitive indicator of recent seafood consumption.

Arsenic↗
PubMed1987

Micronutrient assay for cancer prevention clinical trials: serum retinol, retinyl palmitate, alpha-carotene, and beta-carotene with the use of high-performance liquid chromatography.

Assay of serum levels of retinol, retinyl palmitate, alpha-carotene, and beta-carotene to assess nutritional status, to trials of retinol and/or beta-carotene to assess nutritional status, to monitor compliance with medication schedules, and to conduct toxicity surveillance. The optimal assay method for clinical trial use represents a balance between analytical power and speed/simplicity. Three such methods were evaluated by means of shared samples between two laboratories. Each method required less than 15 minutes per assay and detected all of the analytes of interest. Careful evaluation of calibration materials and procedures permitted different laboratories using different methods to produce results with an interlaboratory variability smaller than the within-laboratory variability for each separate method. Typical precisions for the analytes in serum samples are: retinol, 0.06 relative standard deviation (RSD; standard deviation divided by mean value); retinyl palmitate, 0.08 RSD; alpha-carotene, 0.15 RSD; and beta-carotene, 0.11 RSD. Application of these methods to several hundred samples indicated that retinyl palmitate and beta-carotene levels were indicative of administered retinol and beta-carotene, whereas retinol itself was not. Population variability in pretreatment serum levels of these micronutrients expressed as RSD (retinol, 0.24; alpha-carotene, 1.11; and beta-carotene, 0.98) far exceeded the analytical imprecision in these determinations, confirming that the present assays could meet the needs of current clinical intervention trials.

Carotenoids↗