Interpreting biomonitoring data: Introducing the international human biomonitoring (i-HBM) working group's health-based guidance value (HB2GV) dashboard.

Human biomonitoring (HBM) data measured in specific contexts or populations provide information for comparing population exposures. There are numerous health-based biomonitoring guidance values, but to locate these values, interested parties need to seek them out individually from publications, governmental reports, websites and other sources. Until now, there has been no central, international repository for this information. Thus, a tool is needed to help researchers, public health professionals, risk assessors, and regulatory decision makers to quickly locate relevant values on numerous environmental chemicals. A free, on-line repository for international health-based guidance values to facilitate the interpretation of HBM data is now available. The repository is referred to as the "Human Biomonitoring Health-Based Guidance Value (HB2GV) Dashboard". The Dashboard represents the efforts of the International Human Biomonitoring Working Group (i-HBM), affiliated with the International Society of Exposure Science. The i-HBM's mission is to promote the use of population-level HBM data to inform public health decision-making by developing harmonized resources to facilitate the interpretation of HBM data in a health-based context. This paper describes the methods used to compile the human biomonitoring health-based guidance values, how the values can be accessed and used, and caveats with using the Dashboard for interpreting HBM data. To our knowledge, the HB2GV Dashboard is the first open-access, curated database of HBM guidance values developed for use in interpreting HBM data. This new resource can assist global HBM data users such as risk assessors, risk managers and biomonitoring programs with a readily available compilation of guidance values.

Trends in environmental chemical concentrations in the Canadian population: Biomonitoring data from the Canadian Health Measures Survey 2007-2017.

Ten years of nationally representative biomonitoring data collected between 2007 and 2017 are available from the Canadian Health Measures Survey (CHMS). These data establish baseline environmental chemical concentrations in the general population. Here we sought to evaluate temporal trends in environmental chemical exposures in the Canadian population by quantifying changes in biomarker concentrations measured in the first five two-year cycles of the CHMS. We identified 39 chemicals that were measured in blood or urine in at least three cycles and had detection rates over 50% in the Canadian population. We calculated geometric mean concentrations for each cycle using the survey weights provided. We then conducted analyses of variance to test for linear trends over all cycles. We also calculated the percent difference in geometric means between the first and most recent cycle measured. Of the 39 chemicals examined, we found statistically significant trends across cycles for 21 chemicals. Trends were decreasing for 19 chemicals from diverse chemical groups, including metals and trace elements, phenols and parabens, organophosphate pesticides, per- and polyfluoroalkyl substances, and plasticizers. Significant reductions in chemical concentrations included di-2-ethylhexyl phthalate (DEHP; 75% decrease), perfluorooctane sulfate (PFOS; 61% decrease), perfluorooctanoic acid (PFOA; 58% decrease), dimethylphosphate (DMP; 40% decrease), lead (33% decrease), and bisphenol A (BPA; 32% decrease). Trends were increasing for two pyrethroid pesticide metabolites, including a 110% increase between 2007 and 2017 for 3-phenoxybenzoic acid (3-PBA). No significant trends were observed for the remaining 18 chemicals that included arsenic, mercury, fluoride, acrylamide, volatile organic compounds, and polycyclic aromatic hydrocarbons. National biomonitoring data indicate that concentrations, and therefore exposures, have decreased for many priority chemicals in the Canadian population. Concentrations for other chemical groups have not changed or have increased, although average concentrations remain below thresholds of concern derived from human exposure guidance values. Continued collection of national biomonitoring data is necessary to monitor trends in exposures over time.

Evaluation of human biomonitoring data in a health risk based context: An updated analysis of population level data from the Canadian Health Measures Survey.

In order to characterize exposure of the Canadian population to environmental chemicals, a human biomonitoring component has been included in the Canadian Health Measures Survey (CHMS). This nationally-representative survey, launched in 2007 by the Government of Canada, has measured over 250 chemicals in approximately 30,000 Canadians during the last decade. The capacity to interpret these data at the population level in a health risk context is gradually improving with the development of biomonitoring screening values, such as biomonitoring equivalents (BE) and human biomonitoring (HBM) values. This study evaluates recent population level biomonitoring data from the CHMS in a health risk context using biomonitoring screening values. Nationally representative biomonitoring data for fluoride, selenium, molybdenum, arsenic, silver, thallium, cyfluthrin, 2,4-dichlorophenoxyacetic acid (2,4-D), 3-phenoxybenzoic acid (3-PBA), chlorpyrifos, deltamethrin, bisphenol A, triclosan, acrylamide, cadmium, perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), bromoform, chloroform, benzene, toluene, xylene, ethylbenzene, styrene and tetrachloroethylene were screened as part as this study. For non-cancer endpoints, hazard quotients (HQs) were calculated as the ratio of population level concentrations of a specific chemical at the geometric mean and 95th percentile to the corresponding biomonitoring screening value. Cancer risks were calculated at the 5th, 25th, 50th, 75th and 95th percentiles of the population concentration using BEs based on a risk specific dose. Most of the chemicals analyzed had HQs below 1 suggesting that levels of exposure to these chemicals are not a concern at the population level. However, HQs exceeded 1 in smokers for cadmium, acrylamide and benzene, as well as in the general population for inorganic arsenic, PFOS and PFOA, 3-PBA and fluoride. Furthermore, cancer risks for inorganic arsenic, acrylamide, and benzene at most population percentiles of exposure were elevated (>10-5). Specifically, for inorganic arsenic in the general population, the HQ was 3.13 at the 95th percentile concentration and the cancer risk was 3.4 × 10-4 at the 50th percentile of population concentrations. These results suggest that the levels of exposure in the Canadian population to some of the environmental chemicals assessed might be of concern. The results of this screening exercise support the findings of previous risk assessments and ongoing efforts to reduce risks from exposure to chemicals evaluated as part of this study. Although paucity of biomonitoring screening values for several environmental contaminants may be a limitation to this approach, our assessment contributes to the prioritization of a number of chemicals measured as part of CHMS for follow-up activities such as more detailed characterization of exposure sources.

Leveraging the Canadian Health Measures Survey for environmental health research.

Since 2007, the nationally representative, cross-sectional Canadian Health Measures Survey (CHMS) has collected detailed health and exposure data from more than 25,000 Canadians, including a wide range of chemical biomarkers analyzed in blood, urine, and environmental media. This article highlights the extent to which the CHMS dataset has been used in the peer-reviewed environmental health literature and opportunities for further expanding usage of the dataset. A literature search (2007-2018) was performed to identify peer-reviewed studies that have made substantive use of the CHMS dataset. Studies were analyzed according to the study type, data usage, populations studied, environmental health themes, citation/publication data, and institutional collaborations. A total of 51 environmental-health related CHMS studies were identified, including studies related to indoor and outdoor air quality, the built environment, and chemical and environmental tobacco smoke exposures. Health indicator data are being increasingly exploited, as is the ability to combine cycle datasets over time. Although these studies covered a range of environmental exposures, many CHMS variables remain underutilized. The CHMS dataset provides a valuable portrait of chemical exposures in Canadians of all ages, linked to a wide variety of health indicators. Many opportunities remain to exploit and expand both the use of the dataset and collaborations between Canadian agencies and domestic and international research institutions.

Human biomonitoring reference values for some non-persistent chemicals in blood and urine derived from the Canadian Health Measures Survey 2009-2013.

The Canadian Health Measures Survey collects nationally representative human biomonitoring data on a suite of chemicals and their metabolites, including many non-persistent chemicals. Data has been collected on non-persistent chemicals, including acrylamide, chlorophenols, environmental phenols and triclocarban, organophosphate insecticides, phthalates, polycyclic aromatic hydrocarbon, pyrethroid insecticides, and volatile organic compounds from 2009 to 2013. Using a systematic approach building on the reference interval concept proposed by the International Federation of Clinical Chemistry and Laboratory Medicine and the International Union of Pure and Applied Chemistry, we derive human biomonitoring reference values (RV95s) for these classes of non-persistent chemicals in blood and urine for the general Canadian population. RV95s were derived for biomarkers of non-persistent chemicals with widespread detection in Canadians (>66% detection rate). Samples with urinary creatinine levels outside the recommended range of 0.3-3.0 µg/L were excluded. Reference populations were constructed by applying smoking and fasting as exclusion criteria where appropriate. Age and sex were evaluated as possible partitioning criteria and separate RV95s were derived for sub-populations in cases where partitioning was deemed necessary. Reference values were derived for 40 biomarkers and represent the first set of RV95s for non-persistent chemicals in the general Canadian population. These values provide a measure of the upper margin of background exposure in the general population and can be compared against individual and population human biomonitoring data. RV95s can be used to by public health officials to identify individuals with high exposures, and by risk assessors and risk managers to identify atypical exposures or subpopulations with elevated exposures.

Human biomonitoring reference values derived for persistent organic pollutants in blood plasma from the Canadian Health Measures Survey 2007-2011.

Nationally representative human biomonitoring data on persistent organic pollutants (POPs) including organochlorine pesticides (OCs), polychlorinated biphenyls (PCBs) brominated flame retardants (BFRs) and perfluoroalkyl substances (PFASs) are available through the Canadian Health Measures Survey (CHMS). We have used a systematic approach building on the reference interval concept proposed by the International Federation of Clinical Chemistry and Laboratory Medicine and the International Union of Pure and Applied Chemistry to derive human biomonitoring reference values (RV95s) for selected POPs in blood plasma in the general Canadian population. Biomarkers were chosen based on specific selection criteria including their detection in most Canadians (>66% detection rate). Age and sex were evaluated as possible partitioning criteria and separate RV95s were derived for the sub-populations in cases where partitioning was deemed necessary. RV95s for OCs, PCBs, and BFRs were derived both on a whole weight of blood plasma and on a lipid weight adjusted basis whereas they were derived only on a whole weight basis for PFASs. RV95s ranged from 0.018µg/L (PCB 201) to 21µg/L (perfluorooctane sulfonate) and from 3.1µg/kg lipid (PCB 201) to 1400µg/kg lipid (p,p'-DDE). The 22 RV95s reported in this paper represent the first set of reference values for POPs in the Canadian general population against which individual and population human biomonitoring data may be compared.

An overview of human biomonitoring of environmental chemicals in the Canadian Health Measures Survey: 2007-2019.

Human biomonitoring (HBM) is used to indicate and quantify exposure by measuring environmental chemicals, their metabolites or reaction products in biological specimens. The biomonitoring component of the Canadian Health Measures Survey (CHMS) is the most comprehensive initiative providing general population HBM data in Canada. The CHMS is an ongoing cross-sectional direct measures survey implemented in 2-year cycles. It provides nationally-representative data on health, nutritional status, environmental exposures, and related risks and protective characteristics. The survey follows a robust planning, design and sampling protocol as well as a comprehensive quality assurance and quality control regime implemented for all aspect of the survey to ensure the validity of the HBM results. HBM blood and urine data are available for CHMS cycles 1 (2007-2009), 2 (2009-2011) and 3 (2012-2013). Field collection has been completed for cycle 4 (2014-2015), with cycle 5 (2016-2017) in progress and cycle 6 planning (2018-2019) being finalized. Biomonitoring results for 279 chemicals are expected over the six cycles of the CHMS (220 in individual blood, urine or hair samples, and 59 in pooled serum samples). The chemicals include metals and trace elements, polychlorinated biphenyls (PCBs), organochlorines, flame retardants, perfluoroalkyl substances, volatile organic compounds (VOCs) and metabolites, environmental phenols, triclocarban, acrylamide, pesticides (e.g., triazines, carbamates, organophosphates, phenoxy, pyrethroids) and/or their metabolites, chlorophenols, polycyclic aromatic hydrocarbon (PAH) metabolites, phthalates and alternate plasticizer metabolites, and tobacco biomarkers. Approximately one half of the chemicals measured in individual blood and urine samples over the first three cycles were detected in more than 60% of samples. CHMS biomonitoring data have been used to establish baseline HBM concentrations in Canadians; inform public health, regulatory risk assessment and management decisions; and fulfil national and international reporting requirements. Concurrent efforts are underway in Canada to develop statistically- and risk-based concepts and tools to interpret biomonitoring data.

Human biomonitoring reference values for metals and trace elements in blood and urine derived from the Canadian Health Measures Survey 2007-2013.

Human biomonitoring reference values are statistical estimates that indicate the upper margin of background exposure to a given chemical at a given time. Nationally representative human biomonitoring data on 176 chemicals, including several metals and trace elements, are available in Canada from 2007 to 2013 through the Canadian Health Measures Survey (CHMS). In this work, we used a systematic approach based on the reference interval concept proposed by the International Federation of Clinical Chemistry and Laboratory Medicine and the International Union of Pure and Applied Chemistry to derive reference values (RV95s) for metals and trace elements. These RV95s were derived for blood and urine matrices in the general Canadian population based on the latest biomonitoring data from the CHMS. Biomarkers were chosen based on specific selection criteria, including widespread detection in Canadians (≥66% detection rate). Reference populations were created for each biomarker by applying appropriate exclusion criteria. Age and sex were evaluated as possible partitioning criteria and separate RV95s were derived for the sub-populations in cases where partitioning was deemed necessary. The RV95s for metals and trace elements in blood ranged from 0.18µg/L for cadmium in young children aged 3-5 years to 7900µg/L for zinc in males aged 20-79 years. In the case of urinary biomarkers, the RV95s ranged from 0.17µg/L for antimony in the total population aged 3-79 years to 1400mg/L for fluoride in adults aged 20-79 years. These RV95s represent the first set of reference values for metals and trace elements in the general Canadian population. We compare the RV95s from other countries where available and discuss factors that could influence such comparisons.

Screening of population level biomonitoring data from the Canadian Health Measures Survey in a risk-based context.

Since 2007, the Canadian Health Measures Survey (CHMS) has been collecting biomonitoring data from the general Canadian population and has provided, to date, nationally representative concentrations for hundreds of environmental biomarkers in blood or urine. Biomonitoring Equivalents (BEs) have been developed as tools to help interpret biomonitoring data in a health risk context at a population level. In this paper, BEs are used to relate biomonitoring data from the CHMS (2007-2011) to existing exposure guidance values developed by Health Canada and other government agencies. Chemical-specific hazard quotients (HQs) and/or cancer risk estimates are calculated using existing BEs corresponding to environmental chemicals analyzed in the CHMS. For the majority of environmental chemicals, calculated HQ values are less than 1 indicating exposure is below published exposure guidance values. Individual biomonitoring data for two biomarkers of metal exposure (inorganic arsenic and cadmium) resulted in HQ values exceeding 1 suggesting that exposure may be above existing guidance values for a portion of the population, at least intermittently. This type of analysis may be used by researchers, risk assessors, and risk managers in prioritization efforts.

Toxicity of glyphosate-based pesticides to four North American frog species.

Glyphosate-based herbicides are among the most widely used pesticides in the world. We compared the acute toxicity of the glyphosate end-use formulation Roundup Original to four North American amphibian species (Rana clamitans, R. pipiens, R. sylvatica, and Bufo americanus) and the toxicity of glyphosate technical, the polyethoxylated tallowamine surfactant (POEA) commonly used in glyphosate-based herbicides, and five newer glyphosate formulations to R. clamitans. For R. clamitans, acute toxicity values in order of decreasing toxicity were POEA > Roundup Original > Roundup Transorb > Glyfos AU; no significant acute toxicity was observed with glyphosate technical material or the glyphosate formulations Roundup Biactive, Touchdown, or Glyfos BIO. Comparisons between the four amphibian species showed that the toxicity of Roundup Original varied with species and developmental stage. Rana pipiens tadpoles chronically exposed to environmentally relevant concentrations of POEA or glyphosate formulations containing POEA showed decreased snout-vent length at metamorphosis and increased time to metamorphosis, tail damage, and gonadal abnormalities. These effects may be caused, in some part, by disruption of hormone signaling, because thyroid hormone receptor beta mRNA transcript levels were elevated by exposure to formulations containing glyphosate and POEA. Taken together, the data suggest that surfactant composition must be considered in the evaluation of toxicity of glyphosate-based herbicides.

Expression profiles of novel thyroid hormone-responsive genes and proteins in the tail of Xenopus laevis tadpoles undergoing precocious metamorphosis.

Thyroid hormones (THs) are critical for the growth, development, and homeostasis of many organisms and are necessary for metamorphosis of Xenopus laevis tadpoles. TH-induced metamorphosis requires alterations in the transcriptome and the proteome. However, only a few of the molecular components of this developmental program have been identified and their interrelationship remains unclear. Using a cDNA array comprised of 420 known anuran genes and quantitative PCR, we have identified 93 TH-responsive genes in the tail of premetamorphic tadpoles after exogenous administration of T3. Fifty-three of these mRNA transcripts have not previously been characterized as TH responsive in any species. The gene expression profiles show distinctive temporal patterns with most transcript steady-state levels increasing after induction of metamorphosis. Two-dimensional gel electrophoresis of total protein extracts from the tail shows changes in steady-state levels of many proteins after T3 treatment. Of the up-regulated proteins, 10 were identified by peptide mass mapping. These data identify potential components involved in the regulation of Xenopus tail regression by T3 and begin to address a critical question regarding the interrelationship between the transcriptome and the proteome in TH-dependent developmental processes.

Exposure to the herbicide acetochlor alters thyroid hormone-dependent gene expression and metamorphosis in Xenopus Laevis.

A growing number of substances released into the environment disrupt normal endocrine mechanisms in a wide range of vertebrates. Little is known about the effects and identities of endocrine-disrupting chemicals (EDCs) that target thyroid hormone (TH) action, particularly at the cellular level. Frog tadpole metamorphosis depends completely on TH, which has led to the suggestion of a metamorphosis-based assay for screening potential EDCs. A major mechanism of TH action is the alteration of gene expression via hormone-bound nuclear receptors. To assess the gene expression profiles in the frog model, we designed a novel multispecies frog cDNA microarray. Recently, the preemergent herbicide acetochlor was shown to accelerate 3,5,3 -triiodothyronine (T3)-induced forelimb emergence and increase mRNA expression of thyroid hormone ss receptors in ranid tadpoles. Here we show that T3-induced metamorphosis of Xenopus laevis, a species commonly used in the laboratory, is accelerated upon acute exposure to an environmentally relevant level of acetochlor. The morphologic changes observed are preceded by alterations in gene expression profiles detected in the tadpole tail, and the nature of these profiles suggest a novel mechanism of action for acetochlor.

Distinctive gene profiles occur at key points during natural metamorphosis in the Xenopus laevis tadpole tail.

Thyroid hormones (THs) are essential for tadpole metamorphosis into a juvenile frog; however, a complex interplay between additional hormones and signaling events also contributes to this dramatic developmental phase. A major mechanism of TH action is the nuclear receptor-mediated regulation of gene transcription of responsive genes. By using the precocious metamorphic model, several genes have been identified as TH responsive in the regressing tail. Many of these genes also exhibit altered expression during natural metamorphosis. Although identification of these genes provides insight into the mechanism whereby TH acts, complex interplay between TH and other hormones and the developmental stage-dependency of tissue responses contribute to the timing and coordination of metamorphic events. We investigated the temporal gene expression profile in Xenopus laevis tadpole tails from premetamorphosis through metamorphic climax by using a combination of a novel frog cDNA array containing 420 genes and quantitative real-time PCR. Seventy-nine genes were identified whose steady-state mRNA expression levels were altered in the tadpole tail during natural metamorphosis, of which 34 have previously been identified to be TH responsive in frogs or mammals. Of these genes, 75 clustered into 13 groups that displayed distinct developmental expression profiles. The levels of 28 transcripts were altered during premetamorphosis, 31 during prometamorphosis, and 43 with the onset of tail regression. This work establishes an important baseline for determining the mechanisms whereby tissues undergo differing metamorphic fates.