Hyperkeratosis induced by sunlight degradation products of the major polybrominated biphenyl in Firemaster.

Sunlight photodegradation of 2,2', 4,4', 5,5' -hexabromobiphenyl, the major component of Firemaster, gave a mixture that produces severe hyperkeratosis of the rabbit ear. This component in its pure state does not cause hyperkeratosis. One or more of the four major photolysis products must be responsible for this activity. A similar photodegradation pattern was observed for 2,2', 3,4,4', 5,5' -heptabromobiphenyl, the second largest component of Firemaster.

L-tryptophan implicated in human eosinophilia-myalgia syndrome causes fasciitis and perimyositis in the Lewis rat.

Tryptophan-associated eosinophilia-myalgia syndrome (L-TRP-EMS) is a newly described syndrome which occurred in epidemic fashion in the United States in the summer and fall of 1989. Epidemiologic data has linked the syndrome to intake of L-tryptophan (L-TRP) from one specific manufacturer, but the precise etiologic compound(s) must be established by replication of the syndrome in an appropriate animal model. In this study, implicated L-TRP, United States Pharmacopeia (USP) grade L-TRP, or vehicle was administered by gavage in a blinded fashion for 38 d to female Lewis rats at doses comparable with those ingested by patients who developed the eosinophilia-myalgia syndrome. Animals receiving implicated L-TRP, but not those receiving USP grade L-TRP or vehicle, developed histologic signs consistent with fasciitis and perimyositis, specific pathologic features of human L-TRP-EMS. Peripheral blood eosinophilia was not observed. Hypothalamic corticotropin releasing hormone mRNA levels were lower and plasma corticosterone levels tended to be lower in the animals that received implicated L-TRP. Plasma L-kynurenine was higher in both L-TRP-treated groups compared to the vehicle-treated animals. The female Lewis rat is known to be susceptible to a wide variety of inflammatory diseases. Identification of specific inflammatory changes in this rat following exposure to implicated L-TRP indicates that this animal model will be important in subsequent investigations into the etiology, pathogenesis, and treatment of human L-TRP-EMS.

Environmental chemicals: from the environment to food, to breast milk, to the infant.

Food is a source of exposure to many environmental chemicals found in human milk and other biological specimens. Ingestion of foods containing high amounts of animal fat is the main route of human exposure to lipophilic chemicals, such as persistent organic pollutants, which tend to bioaccumulate in the lipid compartment. Bioaccumulation results in increased exposure of these chemicals for humans, but particularly to breastfeeding infants, who are at the top of the food chain. The extent to which food contributes to a person's overall exposure depends on individual dietary habits and the concentrations of chemical residues in the food. These, in turn, are affected by (1) application methods, (2) properties and amounts of the chemical, and (3) preparation, handling, and the properties of the food. Once the food is ingested by the lactating woman, the chemical's pharmacokinetics and the transport mechanisms producing the movement of solutes across mammary alveolar cells determine the passage of chemicals from the blood to the milk. Thus, several factors affect the presence in human milk of environmental chemicals from dietary sources.

Serum 2,3,7,8-tetrachlorodibenzo-p-dioxin levels of New Zealand pesticide applicators and their implication for cancer hypotheses.

BACKGROUND: The phenoxyherbicide 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) has been widely used by professional pesticide applicators in New Zealand since before 1950. Epidemiologic studies of the risk of cancer and birth defects have been conducted in this group of workers, but little is known about the extent of their exposure to the 2,4,5-T contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent carcinogen in animals. PURPOSE: The objective of this study was to determine whether the blood serum levels of TCDD in a group of professional 2,4,5-T applicators in New Zealand were greater than those of a matched control group not involved in 2,4,5-T spraying. METHODS: Of 548 men employed as professional pesticide applicators in New Zealand from 1979 through 1982, nine were selected who had sprayed pesticides, although not necessarily 2,4,5-T, for at least 180 months. These applicators had sprayed 2,4,5-T for a range of 83-372 months. We measured the blood serum levels of polychlorinated dibenzo-p-dioxins and dibenzofurans, which were substituted with chlorine at the 2,3,7,8 position, in the nine pesticide applicators and in a matched group of nine control subjects. RESULTS: The average serum level of TCDD for applicators was almost 10 times that for the matched control subjects, while the average levels of all other congeners and isomers measured in the two groups did not differ substantially. TCDD levels in eight of the nine applicators were higher than those in the control subjects (mean difference, 47.7 parts per trilion). The variation in TCDD levels among the applicators was related to their duration of work exposure to 2,4,5-T. CONCLUSIONS: On the basis of our findings in these subjects in New Zealand, we conclude that increased risks of cancer from brief exposure to phenoxyherbicides reported in other countries are probably not attributable to the TCDD that contaminates 2,4,5-T. We cannot determine from these results, however, whether TCDD exposure from prolonged use of 2,4,5-T poses significant health risks.

Current serum levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin in phenoxy acid herbicide applicators and characterization of historical levels.

BACKGROUND: Workers who sprayed phenoxy acid herbicides, especially those who sprayed before 1975, may have been exposed to significant amounts of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent animal carcinogen present in herbicide preparations as a contaminant. PURPOSE: The aims of this study were (a) to determine serum levels of TCDD in a representative sample of workers occupationally exposed to the agent during the spraying of phenoxy acid herbicides; (b) to compare serum levels in workers exposed before 1965, when concentrations in herbicide products were unregulated and high, with levels in workers exposed after 1974, when concentrations were lower as a result of government regulations worldwide; and (c) to examine the correlation, if any, between serum levels and duration of employment in spraying. METHODS: Thirty-seven subjects were randomly selected from a group of 654 men who had sprayed the herbicides 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4-dichlorophenoxyacetic acid (2,4-D) in Australia for at least 12 months. The workers were classified as follows: eight who sprayed only before 1965, nine who sprayed only during the period after 1964 and before 1975, and 20 who sprayed during the period after 1974 and before 1991. Serum from the workers was analyzed for TCDD by high-resolution gas chromatography and high-resolution mass spectrometry at a detection limit of 0.6 parts per trillion (ppt) on a lipid-weight basis. In addition, rates of exposure to TCDD were estimated, as were TCDD serum concentrations at termination of employment and intensity of herbicide use. RESULTS: Only one worker, with a serum TCDD level of 34 ppt, had a serum level higher than the maximum level of 26 ppt reported for the general population. Assuming a half-life of 7.1 years, we estimated the mean exposure rates to be 2.7, 2.3, and 0.06 ppt/mo for the three epochs, respectively. We found the highest serum level of TCDD at the time of cessation of employment to be 329 ppt. Calendar period and intensity of use of 2,4,5-T and 2,4-D were statistically significant determinants of rate of exposure to TCDD, but 2,4-D was associated with exposure rate only for the pre-1975 periods. Estimated rates prior to 1965 were more than an order of magnitude higher than those after 1974. CONCLUSION: The highest estimated exposure rate was 20.7 ppt/mo, which suggests that some sprayers may have been exposed to levels comparable with those that produce cancer in laboratory animals.

Serum organochlorine levels and breast cancer: a nested case-control study of Norwegian women.

This study investigated the potential association between organochlorine exposure and breast cancer using stored sera collected from 1973 through 1991 from the Janus Serum Bank in Norway. Breast cancer cases were ascertained prospectively from among 25,431 female serum bank donors. A total of 150 controls were matched to cases by birth dates and dates of sample collection. One g of serum per subject was analyzed for a total of 71 organochlorine compounds. For 6 pesticides [B-hexachlorocyclohexane, heptachlor epoxide, oxychlordane, trans-nonachlor, p, p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene, and p, p'-2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane] and 26 individual polychlorinated biphenyl (PCB) congeners there were >90% of samples over the limit of detection. There was no evidence for higher mean serum levels among cases for any of these compounds, nor any trend of increasing risk associated with higher quartiles of exposure. The remaining compounds (including dieldrin) were analyzed with respect to the proportion of cancer cases and controls having detectable levels; no positive associations were noted in these analyses. Our study did not confirm the recent findings of a Danish study of increased concentrations of dieldrin in the serum of breast cancer cases. The evidence to date on the association between serum organochlorines is not entirely consistent, but there is accumulating evidence that serum levels of p, p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and total PCBs are not important predictors for breast cancer in the general population. Studies to date have not been able to evaluate whether exposure to highly estrogenic, short-lived PCB congeners increases breast cancer risk, nor have they fully evaluated the risk associated with organochlorine exposure in susceptible subgroups or at levels above general population exposure, including women with occupational exposure.

Pancreatic cancer and serum organochlorine levels.

Occupational exposure to p,p'-dichlorodiphenyltrichloroethane (DDT) has been associated with increased pancreatic cancer risk. We measured organochlorine levels in serum obtained at the study enrollment from 108 pancreatic cancer cases and 82 control subjects aged 32-85 years in the San Francisco Bay Area between 1996 and 1998. Cases were identified using rapid case-ascertainment methods; controls were frequency-matched to cases on age and sex via random digit dial and random sampling of Health Care Financing Administration lists. Serum organochlorine levels were adjusted for lipid content to account for variation in the lipid concentration in serum between subjects. Median concentrations of p,p'-dichlorodiphenyldichloroethylene (DDE, 1290 versus 1030 ng/g lipid; P = 0.05), polychlorinated biphenyls (PCBs; 330 versus 220 ng/g lipid; P<0.001), and transnonachlor (54 versus 28 ng/g lipid; P = 0.03) were significantly greater among cases than controls. A significant dose-response relationship was observed for total PCBs (P for trend <0.001). Subjects in the highest tertile of PCBs (> or =360 ng/g lipid) had an odds ratio (OR) of 4.2 [95% confidence interval (CI) = 1.8-9.4] compared to the lowest tertile. The OR of 2.1 for the highest level of p,p'-DDE (95% CI = 0.9-4.7) diminished (OR = 1.1; 95% CI = 0.4-2.8) when PCBs were included in the model. Because pancreatic cancer is characterized by cachexia, the impact of this on the serum organochlorine levels in cases is difficult to predict. One plausible effect of cachexia is bioconcentration of organochlorines in the diminished lipid pool, which would lead to a bias away from the null. To explore this, a sensitivity analysis was performed assuming a 10-40% bioconcentration of organochlorines in case samples. The OR associated with PCBs remained elevated under conditions of up to 25% bioconcentration.

Serum concentrations of organochlorine compounds and the subsequent development of breast cancer.

A nested case-control study was conducted to examine the association between serum concentrations of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE), the primary metabolite of 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT), and polychlorinated biphenyls (PCBs) and the development of breast cancer up to 20 years later. Cases (n = 346) and controls (n = 346) were selected from cohorts of women who donated blood in 1974, 1989, or both, and were matched on age, race, menopausal status, and month and year of blood donation. Analyses were stratified by cohort participation because median DDE and PCB concentrations among the controls were 59 and 147% higher in 1974 than 1989, respectively. Median concentrations of DDE were lower among cases than controls in both time periods [11.7% lower in 1974 (P = 0.06) and 8.6% lower in 1989 (P = 0.41)]. Median concentrations of PCBs were similar among cases and controls [P = 0.21 for 1974 and P = 0.37 for 1989 (Wilcoxon signed rank test)]. The risk of developing breast cancer among women with the highest concentrations of DDE was roughly half that among women with the lowest concentrations, whether based on concentrations in 1974 [odds ratio (OR), 0.50; 95% confidence interval (CI), 0.27-0.89; P(trend) = 0.02] or in 1989 (OR, 0.53; 95% CI, 0.24-1.17; P(trend) = 0.08). The associations between circulating concentrations of PCBs and breast cancer were less pronounced but still in the same direction (1974: OR, 0.68; 95% CI, 0.36-12.9; P(trend) = 0.2; and 1989: OR, 0.73; 95% CI, 0.37-1.46; P(trend) = 0.6). Adjustment for family history of breast cancer, body mass index, age at menarche or first birth, and months of lactation did not materially alter these associations. These associations remained consistent regardless of lactation history and length of the follow-up interval, with the strongest inverse association observed among women diagnosed 16-20 years after blood drawing. Results from this prospective, community-based nested case-control study are reassuring. Even after 20 years of follow-up, exposure to relatively high concentrations of DDE or PCBs showed no evidence of contributing to an increased risk of breast cancer.

Synthesis of thieno[2,3-b]azepin-4-ones as potential antineoplastic agents.

In view of the antitumor activity reported for 7,8-dimethylbenzo[b]azepine-2,5-dione, new isosteric thieno[2,3-b]-azepin-4-ones have been prepared by a Dieckmann ring closure reaction. Substituted 2-amino-3-carbethoxythiophenes were tosylated, or benzoylated, and the corresponding sodium salt was alkylated with ethyl 4-bromobutyrate. The resulting product was cyclized in the presence of sodium hydride, and the azepinones were detosylated with 40% sulfuric acid-acetic acid solution. Preliminary biological data do not indicate any siginificant antineoplastic activity.

Using biological monitoring to assess human exposure to priority toxicants.

Scientifically valid exposure assessment is crucial to risk assessment, risk management, and prevention of environmental disease. Scientists have used three tools to assess exposure: exposure history/questionnaire, environmental monitoring (including personal monitoring), and biological monitoring. Combinations of these tools usually provide the exposure information needed to meet objectives of human studies evaluating the exposure-health effect relationship. Biological monitoring is a capable exposure assessment tool that has provided important information used in public health decisions. We briefly describe how risk assessment and risk management decisions for lead, dioxin, and volatile organic compounds have substantially benefited from exposure information obtained from biological monitoring.

The priority toxicant reference range study: interim report.

The relationship between human exposure to environmental toxicants and health effects is of utmost interest to public health scientists. To define this relationship, these scientists need accurate and precise methods for assessing human exposure and effects. One of the most accurate and precise means of assessing exposure is to measure the level of the toxicant or its primary metabolite in a biologic specimen; this has been defined as measuring the internal dose. This measurement must be quantitative to best study the dose-response relationship. Pertinent questions asked during an exposure assessment include "How do the levels of a given toxicant in a particular population compare with the levels of that toxicant in other populations?" and "What is the prevalence of exposure to that toxicant in other populations?" To answer these questions for two chemical classes of environmental toxicants, we developed state-of-the-art analytic methods and then applied them to measure the levels of 44 environmental toxicants in biologic specimens from 1000 United States residents who participated in the Third National Health and Nutrition Examination Survey (NHANES III). These 1000 people are a cross-sectional subset of the NHANES III population and were selected from urban and rural communities in four regions of the United States; all were between 20 and 59 years of age. This subset is not a probability-based sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans among people eating contaminated home-produced eggs and beef.

We compared serum polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) among residents of two homes to levels among age- and sex-matched comparison subjects. The residents of the two homes consumed contaminated eggs and beef from animals raised at the homes. The animals had greater soil contact than those raised with conventional commercial husbandry practices. The comparison subjects were from a similar rural area, but did not consume home-produced beef and eggs. Serum levels of 2,3,7, 8-substituted tetra-, penta-, and hexaCDDs and penta-, hexa-, and heptaCDFs were increased between 2- and 6-fold in residents from one home; contaminated eggs and beef were consumed by residents for 2-15 years. Elevations were less for those in the other index home, where only home-produced eggs were consumed for 2 years; a 3-fold elevation of 1,2,3,7,8,9-hexaCDD as compared to controls was most apparent. Very strong bivariate correlations among all of the 2,3,7, 8 penta- and hexaCDDs/CDFs were observed. The elevations observed verify that PCDD/PCDF-contaminated food contributed to the body burden of these compounds. The blood levels among the highest exposed participants are generally higher than those observed in other studies of U.S. contaminated-fish consumers and higher than average adipose tissue levels observed in U.S. urban populations. There are sufficient animal toxicologic and human epidemiologic data to recommend that exposures be reduced. In the study area, pentachlorophenol and pentachlorophenol incineration sources have been identified, and the animal contamination and blood elevations probably reflect these sources. Soil reference values and site-specific risk assessments should include estimates of exposures to contamination in home-produced animal products. Such estimates can be verified with limited PCDD/PCDF sampling of animals and humans.

Levels of non-ortho-substituted (coplanar), mono- and di-ortho-substituted polychlorinated biphenyls, dibenzo-p-dioxins, and dibenzofurans in human serum and adipose tissue.

We have measured non-ortho-substituted (coplanar) polychlorinated biphenyl (PCB) levels as well as polychlorinated dibenzo-p-dioxin (PCDD) and polychlorinated dibenzofuran (PCDF) levels in human adipose tissue and serum collected in Atlanta, Georgia. The results show that the concentrations of the coplanar PCBs can be more than an order of magnitude higher than the concentrations of 2,3,7,8-tetrachlorodibenzo-p-dioxin. Our measurements in pooled serum collected in 1982, 1988, and 1989 show a decrease in coplanar PCB levels from 1982 to 1989. We found that the pattern of relative amounts of coplanar PCBs in adipose tissue varied greatly from person to person unlike the PCDD and PCDF patterns, which were more nearly the same. Age was significantly correlated with the concentrations of 2,3,7,8-TCDD,3,3'4,4'-PCB, 3,3',4,4',5-PCB, and 3,3'4,4',5,5'-PCB in adipose tissue. We also measured levels of the mono- and di-ortho chlorine-substituted PCBs in human serum. The levels for some of these PCB congeners were three orders of magnitude higher than the coplanar PCBs, PCDDs, and PCDFs. We used the international toxicity equivalency factors (TEFs) for PCDDs and PCDFs and the TEFs proposed by Safe for PCBs to calculate the 2,3,7,8-TCDD equivalents. Four PCBs (3,3',4,4',5-; 2,3',4,4',5-;2,3,3',4,4'-;2,3,3',4,4',5-) make a larger contribution than 2,3,7,8-TCDD, while four other PCBs (3,3',4,4'5,5'-; 2,2',3,4,4',5'-;2,2',4,4',5,5'-;2,2',3,4,4',5,5'-) make nearly the same contribution as 2,3,7,8-TCDD. The mono-ortho-chlorine-substituted 2,3',4,4',5-PCB, however, is the major contributor to the total 2,3,7,8-TCDD equivalents in general population samples from the United States, Sweden, and Japan.(ABSTRACT TRUNCATED AT 250 WORDS)

2,3,7,8-Tetrachlorodibenzo-p-dioxin plasma levels in Seveso 20 years after the accident.

In 1976, near Seveso, Italy, an industrial accident caused the release of large quantities of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) into the atmosphere, resulting in the highest levels of the toxicant ever recorded in humans. The contaminated area was divided into three zones (A, B, R) corresponding to decreasing TCDD levels in soil, and cohort including all residents was enumerated. The population of the surrounding noncontaminated area (non-ABR) was chosen as referent population. Two decades after the accident. plasma TCDD levels were measured in 62 subjects randomly sampled from the highest exposed zones (A and B) and 59 subjects from non-ABR, frequency matched for age, gender, and cigarette smoking status. Subjects living in the exposed areas have persistently elevated plasma TCDD levels (range = 1.2-89.9 ppt; geometric mean = 53.2 and 11.0 ppt for Zone A and Zone B, respectively). Levels significantly decrease by distance from the accident site (p = 0.0001), down to general population values (4.9 ppt) in non-ABR, thus validating the original zone classification based on environmental measurements. Women have higher TCDD levels than men in the entire study area (p = 0.0003 in Zone B; p = 0.007 in non-ABR). This gender difference persists after adjustment for location within the zone, consumption of meat derived from locally raised animals, age, body mass index, and smoking. There is no evidence for a gender difference in exposure, so variation in metabolism or elimination due to body fat or hormone-related factors may explain this finding. Elevated TCDD levels in women may contribute to adverse reproductive, developmental, and cancer outcomes.

Measurement of children's exposure to pesticides: analysis of urinary metabolite levels in a probability-based sample.

The Minnesota Children's Pesticide Exposure Study is a probability-based sample of 102 children 3-13 years old who were monitored for commonly used pesticides. During the summer of 1997, first-morning-void urine samples (1-3 per child) were obtained for 88% of study children and analyzed for metabolites of insecticides and herbicides: carbamates and related compounds (1-NAP), atrazine (AM), malathion (MDA), and chlorpyrifos and related compounds (TCPy). TCPy was present in 93% of the samples, whereas 1-NAP, MDA, and AM were detected in 45%, 37%, and 2% of samples, respectively. Measured intrachild means ranged from 1.4 microg/L for MDA to 9.2 microg/L for TCPy, and there was considerable intrachild variability. For children providing three urine samples, geometric mean TCPy levels were greater than the detection limit in 98% of the samples, and nearly half the children had geometric mean 1-NAP and MDA levels greater than the detection limit. Interchild variability was significantly greater than intrachild variability for 1-NAP (p = 0.0037) and TCPy (p < 0.0001). The four metabolites measured were not correlated within urine samples, and children's metabolite levels did not vary systematically by sex, age, race, household income, or putative household pesticide use. On a log scale, mean TCPy levels were significantly higher in urban than in nonurban children (7.2 vs. 4.7 microg/L; p = 0.036). Weighted population mean concentrations were 3.9 [standard error (SE) = 0.7; 95% confidence interval (CI), 2.5, 5.3] microg/L for 1-NAP, 1.7 (SE = 0.3; 95% CI, 1.1, 2.3) microg/L for MDA, and 9.6 (SE = 0.9; 95% CI, 7.8, 11) microg/L for TCPy. The weighted population results estimate the overall mean and variability of metabolite levels for more than 84,000 children in the census tracts sampled. Levels of 1-NAP were lower than reported adult reference range concentrations, whereas TCPy concentrations were substantially higher. Concentrations of MDA were detected more frequently and found at higher levels in children than in a recent nonprobability-based sample of adults. Overall, Minnesota children's TCPy and MDA levels were higher than in recent population-based studies of adults in the United States, but the relative magnitude of intraindividual variability was similar for adults and children.

Levels of seven urinary phthalate metabolites in a human reference population.

Using a novel and highly selective technique, we measured monoester metabolites of seven commonly used phthalates in urine samples from a reference population of 289 adult humans. This analytical approach allowed us to directly measure the individual phthalate metabolites responsible for the animal reproductive and developmental toxicity while avoiding contamination from the ubiquitous parent compounds. The monoesters with the highest urinary levels found were monoethyl phthalate (95th percentile, 3,750 ppb, 2,610 microg/g creatinine), monobutyl phthalate (95th percentile, 294 ppb, 162 microg/g creatinine), and monobenzyl phthalate (95th percentile, 137 ppb, 92 microg/g creatinine), reflecting exposure to diethyl phthalate, dibutyl phthalate, and benzyl butyl phthalate. Women of reproductive age (20-40 years) were found to have significantly higher levels of monobutyl phthalate, a reproductive and developmental toxicant in rodents, than other age/gender groups (p < 0.005). Current scientific and regulatory attention on phthalates has focused almost exclusively on health risks from exposure to only two phthalates, di-(2-ethylhexyl) phthalate and di-isononyl phthalate. Our findings strongly suggest that health-risk assessments for phthalate exposure in humans should include diethyl, dibutyl, and benzyl butyl phthalates.

Levels of methyleugenol in a subset of adults in the general U.S. population as determined by high resolution mass spectrometry.

We developed a sensitive and accurate analytical method for quantifying methyleugenol (ME) in human serum. Our method uses a simple solid-phase extraction followed by a highly specific analysis using isotope dilution gas chromatography-high resolution mass spectrometry. Our method is very accurate; its limit of detection is 3.1 pg/g and its average coefficient of variation is 14% over a 200-pg/g range. We applied this method to measure serum ME concentrations in adults in the general U.S. population. ME was detected in 98% of our samples, with a mean ME concentration of 24 pg/g (range < 3.1-390 pg/g). Lipid adjustment of the data did not alter the distribution. Bivariate and multivariate analyses using selected demographic variables showed only marginal relationships between race/ethnicity and sex/fasting status with serum ME concentrations. Although no demographic variable was a good predictor of ME exposure or dose, our data indicate prevalent exposure of U.S. adults to ME. Detailed pharmacokinetic studies are required to determine the relationship between ME intake and human serum ME concentrations.

Case studies of the use of biomarkers to assess exposures.

Because many environmental toxicants are ubiquitous, humans are continuously exposed to them. At other times, certain populations may be more highly exposed to these toxicants from point sources. The evaluation of the degree of the exposure to either a population or an individual is frequently based on indirect surrogates of exposure, such as questionnaire data on time-activities and/or concentrations measured in environmental media. We prefer to assess the degree of the exposure to a given toxicant by measuring the concentration of the toxicant, its metabolite(s), or reaction product(s) in human specimens. Then by applying pharmacokinetic information for that toxicant, we can best reconstruct the exposure scenario. These data are then compared to reference range levels of these toxicants in the preferred biologic specimen. The development and uses of the reference range data are exemplified by case studies including potential exposure to dioxin and solvents.

Assessing children's exposure to hazardous environmental chemicals: an overview of selected research challenges and complexities.

There is renewed interest in the United States regarding characterization of children's exposures to hazardous environmental chemicals. Many studies are currently underway that use novel and innovative approaches to assess childhood exposures to a variety of toxic chemicals, including both persistent and nonpersistent compounds. This article reviews some of the critical challenges that can impede scientifically rigorous studies designed to measure children's environmental exposures. The discussion briefly examines three topical areas: administrative issues (IRB approval, participant incentives, community involvement, and communication of results to research participants and stakeholders); data-collection issues (identifying and recruiting children/families, measuring actual exposures/doses); and issues related to chemical analysis of biological samples (examples of chemicals and chemical classes that can be measured in human tissue and excreta, effects of a child's age on the type and amount of biological samples available for analysis). These research complexities are discussed in the context of developing more effective and efficient exposure assessment methods.

Improving exposure assessment by monitoring human tissues for toxic chemicals.

Typically, the availability of appropriate data to estimate human exposures to toxic chemicals is scarce. Consequently, exposure assessments are often based on indirect surrogates of exposure, such as a combination of questionnaire data on time-activities and concentrations of toxic chemicals measured in environmental media (e.g., air, water, food, soil, dust). Recent advances, however, make it technically feasible and relatively affordable to measure low levels of multiple toxic chemicals in accessible human tissues (e.g., blood, urine). The increasing availability of biological markers for exposure, along with improvements in pharmacokinetic understanding, present new opportunities to estimate exposure from human tissue measurements and from knowledge of intake and uptake parameters. Biological monitoring provides exposure information that is usually complementary to the type of exposure information obtained from environmental monitoring. Biological and environmental monitoring can be used separately or together in order to meet desired objectives. We present here a discussion of the value of biological monitoring for improving exposure assessment. We emphasize the role of biological monitoring in identifying high-priority exposures, evaluating the effectiveness of intervention and prevention efforts, identifying at-risk subpopulations, recognizing time trends in population exposures, establishing reference ranges of tissue concentrations, and providing integrated dose measurements.