Serum concentration trends and apparent half-lives of per- and polyfluoroalkyl substances (PFAS) in Australian firefighters.

BACKGROUND: Per- and polyfluoroalkyl substances (PFASs) are persistent manmade compounds used in aqueous film forming foam (AFFF). The extensive use of AFFF has led to widespread environmental PFAS contamination and exposures of firefighters. OBJECTIVES: To determine PFAS blood serum concentration trends and apparent serum half-lives in firefighters after the replacement of AFFF. METHODS: Current and former employees of an Australian corporation providing firefighting services, where AFFF formulations had been used since the 1980s up until 2010, were recruited in 2018-2019 to participate in this study. Special focus was put on re-recruiting participants who had provided blood samples five years prior (2013-2014). Participants were asked to provide a blood sample and fill in a questionnaire. Serum samples were analysed for 40 different PFASs using HP LC-MS/MS. RESULTS: A total of 799 participants provided blood samples in 2018-2019. Of these, 130 previously provided blood serum in 2013-2014. In 2018-2019, mean (arithmetic) serum concentrations of perfluorooctane sulfonate (PFOS, 27 ng/mL), perfluoroheptane sulfonate (PFHpS, 1.7 ng/mL) and perfluorohexane sulfonate (PFHxS, 14 ng/mL) were higher than the levels in the general Australian population. Serum concentrations were associated with the use of PFOS/PFHxS based AFFF. Participants who commenced service after the replacement of this foam had serum concentrations similar to those in the general population. Mean (arithmetic) individual apparent half-lives were estimated to be 5.0 years (perfluorooctanoic acid (PFOA)), 7.8 years (PFHxS), 7.4 years (PFHpS) and 6.5 years (PFOS). CONCLUSION: This study shows how workplace interventions such as replacement of AFFF can benefit employees at risk of occupational exposure.

Per- and polyfluoroalkyl substances (PFAS) in Australia: Current levels and estimated population reference values for selected compounds.

BACKGROUND: Increased public awareness of PFAS contamination in Australia has resulted in serum biomonitoring efforts in individuals in potentially affected communities. However, population-based reference values for assessing whether individual results exceed the typical range in the Australian general population are not currently available. OBJECTIVE: Estimate population upper bound reference values based on updated serum PFAS concentrations in pooled samples from southeast Queensland, Australia and population variation observed in the US National Health and Nutrition Examination Survey (NHANES) datasets. METHODS: We calculated ratios of 95th percentile to arithmetic mean (P95:AM ratios) using data from the NHANES 2013-14 and 2015-16 cycle samples for frequently detected PFASs: PFOA, linear and branched PFOS, perfluorononanoate (PFNA), perfluorodecanoate (PFDA), and perfluorohexanesulfonate (PFHxS). We estimated Australian age-specific means for PFAS using pooled serum samples collected in 2014-15 and 2016-17. We used the P95:AM ratios to estimate 95th percentile concentrations in the Australian population based on the results of the 2016-17 pooled samples. RESULTS AND CONCLUSIONS: P95:AM ratios for each PFAS were similar across NHANES cycle and age group, so overall compound-specific ratios were estimated for PFOA (2.1), PFNA (2.4), PFDA (2.7), PFHxS (2.7), and linear (2.4) and summed PFOS (2.3). Australian mean PFAS concentrations continued previously reported declining trends. The estimated P95 values can be used as preliminary substitutes for more rigorous population reference values to identify samples with clearly elevated serum PFAS concentrations in Australian biomonitoring efforts. Given uncertainties and variability inherent in this evaluation, the estimated P95 values should be interpreted with caution. Mean and estimated P95 serum PFAS concentrations in Australia should continue to be monitored to document declining trends in population serum concentrations.

Perfluorinated alkyl acids in the serum and follicular fluid of UK women with and without polycystic ovarian syndrome undergoing fertility treatment and associations with hormonal and metabolic parameters.

Women with polycystic ovarian syndrome (PCOS) undergoing treatment for infertility could be a sensitive subpopulation for endocrine effects of exposure to perfluorinated alkyl acids (PFAAs), persistent organic pollutants with potential endocrine activity. Women with, PCOS (n = 30) and age- and BMI-matched controls (n = 29) were recruited from a UK fertility clinic in 2015. Paired serum and follicular fluid samples were collected and analysed for 13 PFAAs. Sex steroid and thyroid hormones, and metabolic markers were measured and assessed for associations with serum PFAAs. Four PFAAs were detected in all serum and follicular fluid samples and concentrations in the two matrices were highly correlated (R2 > 0.95): perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonate (PFHxS), and perfluorononanoic acid (PFNA). Serum PFOS was positively associated with age (1 ng/mL per yr, p < 0.05) and was higher in PCOS cases than controls (geometric mean [GM] 3.9 vs. 3.1 ng/mL, p < 0.05) and in women with irregular vs. regular menstrual cycles (GM 3.9 vs. 3.0 ng/mL, p = 0.01). After adjustment for confounders, serum testosterone was significantly associated with PFOA, PFHxS, PFNA, and the molar sum of the four frequently detected serum PFAAs (approximately 50 percent increase per ln-unit) among controls but not PCOS cases. HbA1c in PCOS cases was inversely associated with serum PFOA, PFHxs, and sum of PFAAs (2-3 mmol/mol per ln-unit). In controls, fasting glucose was positively associated with serum PFOA and sum of PFAAs (0.25 nmol/L per ln-unit increase in PFAAs). Few other associations were observed. The analyses and findings here should be considered exploratory in light of the relatively small sample sizes and large number of statistical comparisons conducted. However, the data do not suggest increased sensitivity to potential endocrine effects of PFAAs in PCOS patients.

Mortality risk among workers with exposure to dioxins.

BACKGROUND: In several studies, dioxin exposure has been associated with increased risk from several causes of death. AIMS: To compare the mortality experience of workers exposed to dioxins during trichlorophenol (TCP) and pentachlorophenol (PCP) production to that of the general population and to examine mortality risk by estimated exposure levels. METHODS: A retrospective cohort study which followed up workers' vital status from 1940 to 2011, with serum surveys to support estimation of historical dioxin exposure levels. RESULTS: Among the 2192 study subjects, there were nine deaths in TCP workers from acute non-lymphatic leukaemia [standardized mortality ratio (SMR) = 2.88, 95% confidence interval (CI) 1.32-5.47], four mesothelioma deaths (SMR = 5.12, 95% CI 1.39-13.10) and four soft tissue sarcoma (STS) deaths (SMR = 3.08, 95% CI 0.84-7.87). In PCP workers, there were eight deaths from non-Hodgkin's lymphoma (SMR = 1.92, 95% CI 0.83-3.79), 150 from ischaemic heart disease (SMR = 1.20, 95% CI 1.01-7.89) and five from stomach ulcers (SMR = 3.38, 95% CI 1.10-7.89). There were no trends of increased mortality with increased dioxin exposure except for STS and 2,3,7,8-tetrachlorodibenzo-p-dioxin levels. This finding for STS should be interpreted with caution due to the small number of deaths and the uncertainty in diagnosis and nosology. CONCLUSIONS: While some causes of death were greater than expected, this study provides little evidence of increased risk when dioxin exposures are considered.

Interpreting biomonitoring data for 2,4-dichlorophenoxyacetic acid: Update to Biomonitoring Equivalents and population biomonitoring data.

Urinary biomonitoring data for 2,4-dichlorophenoxyacetic acid (2,4-D) reflect aggregate population exposures to trace 2,4-D residues in diet and the environment. These data can be interpreted in the context of current risk assessments by comparison to a Biomonitoring Equivalent (BE), which is an estimate of the average biomarker concentration consistent with an exposure guidance value such as the US EPA Reference Dose (RfD). BE values are updated here from previous published BE values to reflect a change in the US EPA RfD. The US EPA RfD has been updated to reflect a revised point of departure (POD) based on new information from additional toxicological studies and updated assessment of applicable uncertainty factors. In addition, new biomonitoring data from both the US National Health and Nutrition Examination Survey (NHANES) and the Canadian Health Measures Survey (CHMS) have been published. The updated US EPA chronic RfD of 0.21 mg/kg-d results in updated BE values of 10,500 and 7000 µg/L for adults and children, respectively. Comparison of the current population-representative data to these BE values shows that upper bound population biomarker concentrations are more than 5000-fold below BE values corresponding to the updated US EPA RfD. This biomonitoring-based risk assessment supports the conclusion that current use patterns in the US and Canada result in incidental exposures in the general population that can be considered negligible in the context of the current 2,4-D risk assessment.

Biomonitoring Equivalents for interpretation of urinary fluoride.

Exposure to fluoride is widespread due to its natural occurrence in the environment and addition to drinking water and dental products for the prevention of dental caries. The potential health risks of excess fluoride exposure include aesthetically unacceptable dental fluorosis (tooth mottling) and increased skeletal fragility. Numerous organizations have conducted risk assessments and set guidance values to represent maximum recommended exposure levels as well as recommended adequate intake levels based on potential public health benefits of fluoride exposure. Biomonitoring Equivalents (BEs) are estimates of the average biomarker concentrations corresponding to such exposure guidance values. The literature on daily urinary fluoride excretion rates as a function of daily fluoride exposure was reviewed and BE values corresponding to the available US and Canadian exposure guidance values were derived for fluoride in urine. The derived BE values range from 1.1 to 2.1mg/L (1.2-2.5µg/g creatinine). Concentrations of fluoride in single urinary spot samples from individuals, even under exposure conditions consistent with the exposure guidance values, may vary from the predicted average concentrations by several-fold due to within- and across-individual variation in urinary flow and creatinine excretion rates and due to the rapid elimination kinetics of fluoride. Thus, the BE values are most appropriately applied to screen population central tendency estimates for biomarker concentrations rather than interpretation of individual spot sample concentrations.

Application of pharmacokinetic modelling for 2,3,7,8-tetrachlorodibenzo-p-dioxin exposure assessment.

Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans, and mono- and non-ortho polychlorinated biphenyls (dioxin-like PCBs) are identified as a family or group of organic compounds known as 'dioxins' or dioxin-like chemicals (DLCs). The most toxic member of this group is 2,3,7,8-tetrachlorodibenzo-(p)-dioxin (TCDD). Historically, DLCs have caused a variety of negative human health effects, but a disfiguring skin condition known as chloracne is the only health effect reported consistently. As part of translational research to make computerized models accessible to health risk assessors, the Concentration- and Age-Dependent Model (CADM) for TCDD was recoded in the Berkeley Madonna simulation language. The US Agency for Toxic Substances and Disease Registry's computational toxicology laboratory used the recoded model to predict TCDD tissue concentrations at different exposure levels. The model simulations successfully reproduced the National Health and Nutrition Examination Survey (NHANES) 2001-2002 TCDD data in age groups from 6 to 60 years and older, as well as in other human datasets. The model also enabled the estimation of lipid-normalized serum TCDD concentrations in breastfed infants. The model performed best for low background exposures over time compared with a high acute poisoning case that could due to the large dose and associated liver toxicity. Hence, this model may be useful for interpreting human biomonitoring data as a part of an overall DLC risk assessment.

"Intrinsic" elimination rate and dietary intake estimates for selected indicator PCBs: toxicokinetic modeling using serial sampling data in US subjects, 2005-2010.

Changes in measured concentrations of persistent compounds such as polychlorinated biphenyls (PCBs) in an individual over time reflect not only intrinsic elimination rates but also any ongoing intake of the compounds and changes in the volume of distribution. Thus, "apparent" elimination rates calculated from data on changes in serum lipid-adjusted concentration may over- or under-estimate the "intrinsic" elimination rates for such compounds. Serum PCB concentrations were measured in 43 individuals approximately 5years apart. Changes in measured concentrations and body weights were used to estimate mass-based apparent elimination rates. The changes in estimated body mass of PCBs 105, 118, 138, 153, and 180 were input into a simple first-order model employing previously estimated intrinsic elimination rates to estimate congener-specific average dietary intake rates over the period between samples. Calculated median dietary intakes were compared to previous estimates. Intrinsic elimination rates were adjusted for two congeners. The analyses support central tendencies of intrinsic elimination rates of approximately 5years for PCBs 105 and 118, 11years for PCB 138, 14.4years for PCB 153, and 20years or more for PCB 180. Estimated dietary intakes for this population and time period depend on the assumed intrinsic elimination rates and range from 0.1ngkg(-1)d(-1) for PCB 105 to approximately 1-2ngkg(-1)d(-1) for PCB 180. Estimated body burdens of PCB 180 changed very little over the five-year period, suggesting near steady-state exposure levels. As a result, estimates for both elimination half-life and ongoing intake rates for this congener are highly uncertain.

Relationships of chemical concentrations in maternal and cord blood: a review of available data.

The developing fetus is likely to be exposed to the same environmental chemicals as the mother during critical periods of growth and development. The degree of maternal-fetal transfer of chemical compounds will be affected by chemical and physical properties such as lipophilicity, protein binding, and active transport mechanisms that influence absorption and distribution in maternal tissues. However, these transfer processes are not fully understood for most environmental chemicals. This review summarizes reported data from more than 100 studies on the ratios of cord:maternal blood concentrations for a range of chemicals including brominated flame-retardant compounds, polychlorinated biphenyls (PCB), polychlorinated dibenzodioxins and dibenzofurans, organochlorine pesticides, perfluorinated compounds, polyaromatic hydrocarbons, metals, and tobacco smoke components. The studies for the chemical classes represented suggest that chemicals frequently detected in maternal blood will also be detectable in cord blood. For most chemical classes, cord blood concentrations were found to be similar to or lower than those in maternal blood, with reported cord:maternal ratios generally between 0.1 and 1. Exceptions were observed for selected brominated flame-retardant compounds, polyaromatic hydrocarbons, and some metals, for which reported ratios were consistently greater than 1. Careful interpretation of the data in a risk assessment context is required because measured concentrations of environmental chemicals in cord blood (and thus the fetus) do not necessarily imply adverse effects or risk. Guidelines and recommendations for future cord:maternal blood biomonitoring studies are discussed.

Short term variability in urinary bisphenol A in Australian children.

Used frequently in food contact materials, bisphenol A (BPA) has been studied extensively in recent years, and ubiquitous exposure in the general population has been demonstrated worldwide. Characterizing within- and between-individual variability of BPA concentrations is important for characterizing exposure in biomonitoring studies, and this has been investigated previously in adults, but not in children. The aim of this study was to characterize the short-term variability of BPA in spot urine samples in young children. Children aged ≥2-<4 years (n=25) were recruited from an existing cohort in Queensland, Australia, and donated four spot urine samples each over a two day period. Samples were analysed for total BPA using isotope dilution online solid phase extraction-liquid chromatography-tandem mass spectrometry, and concentrations ranged from 0.53 to 74.5 ng/ml, with geometric mean and standard deviation of 2.70 ng/ml and 2.94 ng/ml, respectively. Sex and time of sample collection were not significant predictors of BPA concentration. The between-individual variability was approximately equal to the within-individual variability (ICC=0.51), and this ICC is somewhat higher than previously reported literature values. This may be the result of physiological or behavioural differences between children and adults or of the relatively short exposure window assessed. Using a bootstrapping methodology, a single sample resulted in correct tertile classification approximately 70% of the time. This study suggests that single spot samples obtained from young children provide a reliable characterization of absolute and relative exposure over the short time window studied, but this may not hold true over longer timeframes.

Mode of action and dose-response framework analysis for receptor-mediated toxicity: The aryl hydrocarbon receptor as a case study.

Dioxins and dioxin-like compounds are tumor promoters that cause liver cancer in rats and mice. The aryl hydrocarbon receptor (AHR) has been implicated as a key component in this tumor promotion response. Despite extensive knowledge of the toxicology of dioxins, no mode of action (MOA) hypothesis for their tumorigenicity has been formally documented using the Human Relevance MOA framework developed by the International Programme on Chemical Safety (IPCS). To address this information gap, an expert panel was convened as part of a workshop on receptor-mediated liver tumorigenicity. Liver tumors induced by ligands of the AHR were assessed using data for dioxins and related chemicals as a case study. The panel proposed a MOA beginning with sustained AHR activation, eventually leading to liver tumors via a number of other processes, including increased cell proliferation of previously initiated altered hepatic foci, inhibition of intrafocal apoptosis and proliferation of oval cells. These processes have been identified and grouped as three key events within the hepatocarcinogenic MOA: (1) sustained AHR activation, (2) alterations in cellular growth and homeostasis and (3) pre-neoplastic tissue changes. These key events were identified through application of the Bradford-Hill considerations in terms of both their necessity for the apical event/adverse outcome and their human relevance. The panel identified data supporting the identification and dose-response behavior of key events, alteration of the dose-response by numerous modulating factors and data gaps that potentially impact the MOA. The current effort of applying the systematic frameworks for identifying key events and assessing human relevance to the AHR activation in the tumorigenicity of dioxins and related chemicals is novel at this time. The results should help direct future regulatory efforts and research activities aimed at better understanding the potential human cancer risks associated with dioxin exposure.

Age-related trends in urinary excretion of bisphenol A in Australian children and adults: evidence from a pooled sample study using samples of convenience.

Bisphenol A (BPA or 4,4'-(propane-2,2-diyl)diphenol) is a chemical intermediate in the production of polycarbonate and epoxy resins, and is used in a wide range of applications. BPA has attracted significant attention in the past decade due to its frequency of detection in human populations worldwide, and has demonstrated animal toxicity and potential impact on human health, particularly during critical periods of development. The aim of this study was to perform a preliminary assessment of age-related trends in urinary concentration and to estimate daily excretion of BPA in Australian children (aged >0 to <5 yr) and adults (≥15 to <75 yr). This was achieved using 79 samples pooled by age and gender, created from 868 individual samples of convenience collected as part of routine, community-based pathology testing. Total BPA was analyzed using online solid phase extraction (SPE)-liquid chromatography tandem mass spectrometry (LC-MS/MS) and detected in all samples with a range of 0.65-265 ng/ml. No significant differences were observed between males and females. A urine flow model was constructed from published values and was used to provide an estimate of daily excretion per unit body weight for each pooled sample. The daily excretion estimates ranged from 26.2 to 18,200 ng/kg-d for children, and from 20.1 to 165 ng/kg-d for adults. Urinary concentrations and estimated excretion rates were inversely associated with age, and estimated daily excretion in infants and young children was significantly higher than in adults (geometric mean: 107 and 47.0 ng/kg-d, respectively). Higher excretion of BPA in children may be explained by their higher food consumption relative to body weight compared to adults and adolescents, and may also reflect alternative exposure pathways and sources.

Physiologically based pharmacokinetic model for humans orally exposed to chromium.

A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in humans. Compartments were included for gastrointestinal lumen, oral mucosa, stomach, small intestinal tissue, blood, liver, kidney, bone, and a combined compartment for remaining tissues. As chronic exposure to high concentrations of Cr(VI) in drinking water cause small intestinal cancer in mice, the toxicokinetics of Cr(VI) in the upper gastrointestinal tract of rodents and humans are important for assessing internal tissue dose in risk assessment. Fasted human stomach fluid was collected and ex vivo Cr(VI) reduction studies were conducted and used to characterize reduction of Cr(VI) in human stomach fluid as a mixed second-order, pH-dependent process. For model development, toxicokinetic data for total chromium in human tissues and excreta were identified from the published literature. Overall, the PBPK model provides a good description of chromium toxicokinetics and is consistent with the available total chromium data from Cr(III) and Cr(VI) exposures in typical humans (i.e., model predictions are within a factor of three for approximately 86% of available data). By accounting for key species differences, sources of saturable toxicokinetics, and sources of uncertainty and variation, the rodent and human PBPK models can provide a robust characterization of toxicokinetics in the target tissue of the small intestine allowing for improved health risk assessment of human populations exposed to environmentally-relevant concentrations.

Physiologically based pharmacokinetic model for rats and mice orally exposed to chromium.

A multi-compartment physiologically based pharmacokinetic (PBPK) model was developed to describe the behavior of Cr(III) and Cr(VI) in rats and mice following long-term oral exposure. Model compartments were included for GI lumen, oral mucosa, forestomach/stomach, small intestinal mucosa (duodenum, jejunum, ileum), blood, liver, kidney, bone, and a combined compartment for remaining tissues. Data from ex vivo Cr(VI) reduction studies were used to characterize reduction of Cr(VI) in fed rodent stomach fluid as a second-order, pH-dependent process. For model development, tissue time-course data for total chromium were collected from rats and mice exposed to Cr(VI) in drinking water for 90 days at six concentrations ranging from 0.1 to 180 mg Cr(VI)/L. These data were used to supplement the tissue time-course data collected in other studies with oral administration of Cr(III) and Cr(VI), including that from recent NTP chronic bioassays. Clear species differences were identified for chromium delivery to the target tissue (small intestines), with higher concentrations achieved in mice than in rats, consistent with small intestinal tumor formation, which was observed upon chronic exposures in mice but not in rats. Erythrocyte:plasma chromium ratios suggest that Cr(VI) entered portal circulation at drinking water concentrations equal to and greater than 60 mg/L in rodents. Species differences are described for distribution of chromium to the liver and kidney, with liver:kidney ratios higher in mice than in rats. Overall, the PBPK model provides a good description of chromium toxicokinetics, with model predictions for tissue chromium within a factor of 3 for greater than 80% of measurements evaluated. The tissue data and PBPK model predictions indicate a concentration gradient in the small intestines (duodenum > jejunum > ileum), which will be useful for assessing the tumor response gradient observed in mouse small intestines in terms of target tissue dose. The rodent PBPK model presented here, when used in conjunction with a human PBPK model for Cr(VI), should provide a more robust characterization of species differences in toxicokinetic factors for assessing the potential risks associated with low-dose exposures of Cr(VI) in human populations.

Correlates of serum dioxin to self-reported exposure factors.

The aim of the current analysis was to examine the determinates of lipid-adjusted body levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) from occupational histories, age, body mass index, and self-reported information from a questionnaire. We collected serum from 346 workers at a New Zealand chemical plant that manufactured and formulated the herbicide, 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Age, body mass index, and employment history were significant determinates of TCDD. The self-reported data on occupation, residence, and general diet were not predictive of serum levels and we observed no evidence of increased TCDD levels from living close to the site. For participants with putative occupational exposure, employment history and personal factors were important to understand the range of TCDD serum levels. For employees without direct occupational exposure, and resulting lower dioxin levels, we recommend further efforts to develop and validate questionnaires to better evaluate environmental sources of dioxins.

A pilot study of oral bioavailability of dioxins and furans from contaminated soils: Impact of differential hepatic enzyme activity and species differences.

An in vivo pilot study of the oral bioavailability of polychlorinated dibenzo-p-dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in two soils with distinct congener profiles (one dominated by PCDDs, the other by PCDFs) was conducted in rats and juvenile swine. The pilot study revealed potential confounding of relative bioavailability estimates compared to bioavailability in spiked corn oil gavage for tetrachlorodibenzofuran (TCDF) in the rat study due to differential EROD induction between groups receiving soil and those receiving spiked control PCDDs/PCDFs. A follow-up study in rats with the furan-contaminated soil was then conducted with reductions in the spiked control doses to 20%, 50% and 80% of the soil-feed dose in order to bracket hepatic enzyme induction levels in the soil group. When hepatic enzyme induction was matched between the soil and spiked control groups, the apparent relative bioavailability for TCDF was reduced significantly. Overall, after controlling for hepatic enzyme induction, estimates of relative bioavailability in rats and swine differed for the two soils. In the rat study, the relative bioavailability of the two soils were approximately 37% and 60% compared to corn oil administration for the PCDD- and PCDF- dominated soils, respectively, on a TEQ basis. In swine, both soils demonstrated relative bioavailability between 20% and 25% compared to administration in corn oil. These species differences and experimental design issues, such as controlling for differential enzyme induction between corn oil and soil-feed animals in a bioavailability study, are relevant to risk assessment efforts where relative bioavailability inputs are important for theoretical exposure and risk characterization.

Age-specific reference ranges for polychlorinated biphenyls (PCB) based on the NHANES 2001-2002 survey.

The Centers for Disease Control and Prevention (CDC) conducted analyses for 34 polychlorinated biphenyl (PCB) congeners in blood samples collected from a statistically representative sample of the U.S. population during the National Health and Nutrition Examination Survey (NHANES) and reported overall population percentiles. Because the serum concentrations of many persistent organochlorine compounds are strongly age dependent, data were analyzed from the NHANES 2001-2002 sampling cycle to identify age-specific reference ranges for the measured congeners on a lipid-adjusted serum basis. In addition, reference ranges were estimated for the sum of the 34 measured PCB congeners. Because many congeners were frequently nondetectable, estimates for summed PCB levels are dependent upon the assumption used to replace nondetectable concentrations in the calculation. The effect of nondetects on the summed congeners totals is particularly strong for younger ages. The NHANES 2001-2002 PCB serum data demonstrate strong age-related trends, with older individuals displaying higher concentrations of most congeners and of summed PCB congeners. These age-specific reference ranges for PCB concentrations are critical for accurate interpretation of measured serum concentrations of PCB congeners in individuals.

Biomonitoring equivalents: a screening approach for interpreting biomonitoring results from a public health risk perspective.

Advances in both sensitivity and specificity of analytical chemistry have made it possible to quantify substances in human biological specimens, such as blood, urine, and breast milk, in specimen volumes that are practical for collection from individuals. Research laboratories led by the Centers for Disease Control and Prevention (CDC) in its series National Report on Human Exposure to Environmental Chemicals [Centers for Disease Control and Prevention (CDC), 2005. Third National Report on Human Exposure to Environmental Chemicals. NCEH Pub. No. 05-0570.] are dedicating substantial resources to designing and conducting human biomonitoring studies and compiling biomonitoring data for the general population. However, the ability to quantitatively interpret the results of human biomonitoring in the context of a health risk assessment currently lags behind the analytical chemist's ability to make such measurements. The traditional paradigm for human health risk assessment of environmental chemicals involves comparing estimated daily doses to health-based criteria for acceptable, safe, or tolerable daily intakes (for example, reference doses [RfDs], tolerable daily intakes [TDIs], or minimal risk levels [MRLs]) to assess whether estimated doses exceed such health screening levels. However, biomonitoring efforts result in measured chemical concentrations in biological specimens (the result of absorption, distribution, metabolism and excretion of administered doses) rather than estimated intake doses. Quantitative benchmarks of acceptable or safe concentrations in biological specimens (analogous to RfDs, TDIs, or MRLs) needed to interpret these levels exist for very few chemicals of environmental interest. This paper discusses issues inherent in converting existing health screening benchmarks based on intake doses to screening levels for evaluating biomonitoring data, and presents methods and approaches that can be used to derive such screening levels (termed "Biomonitoring Equivalents," or BEs) for a range of chemicals and biological media.

Sex ratio of the offspring of Sprague-Dawley rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in utero and lactationally in a three-generation study.

Reports of a decreased male/female sex ratio in children born to males exposed to TCDD in Seveso, Italy, at a young age have sparked examinations of this endpoint in other populations exposed to TCDD or related compounds. Overall, the male/female sex ratio results reported in these studies, with slightly different age-exposed male populations, have shown mixed results. Experimental studies of the effects of in utero exposure to TCDD in laboratory animals have reported no effect on the f(1) sex ratio and mixed results for the sex ratio of the f(2) generation. In order to better understand the potential effects of TCDD on second generation sex ratio, we retrieved archived data from a comprehensive three-generation feeding study of TCDD in rats that was conducted and published in the 1970s, but which did not publish data on sex ratio of the offspring [Murray, F.J., Smith, F.A., Nitschke, K.D., Humiston, C.G., Kociba, R.J., Schwetz, B.A., 1979. Three-generation reproduction study of rats given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in the diet. Toxicol. Appl. Pharmacol. 50, 241-252]. A re-examination of the original Murray et al. data found no statistically significant treatment-related changes in postnatal day 1 sex ratio in any generation of treated animals, consistent with one other relatively large study reporting on this endpoint. We discuss mechanistic data underlying a potential effect of TCDD on this endpoint. We conclude that the inconsistency in findings on sex ratio of the offspring of male rats exposed to TCDD in utero is likely due to random variation associated with a relatively small sample size, although differences between studies in strain of rat, dose regimen, and day of ascertainment of sex ratio cannot be ruled out.