Development of an observational exposure human biomonitoring study to assess Canadian children's DEET exposure during protective use.

Biomonitoring data of N,N-diethyl-meta-toluamide (DEET) in children is scarce and limited to controlled exposure and surveillance studies. We conducted a 24-hour observational exposure and human biomonitoring study designed to estimate use of and exposure to DEET-based insect repellents by Canadian children in an overnight summer camp setting. Here, we present our study design and methodology. In 2019, children between the ages of 7 and 13 took part in the study (n = 126). Children controlled their use of DEET-based insect repellents, and provided an account of their activities at camp that could impact insect repellent absorption. Children provided a total of 389 urine samples throughout the study day, and reported the time that they applied insect repellent, which allowed us to contextualize urinary DEET and metabolite concentrations with respect to the timing of insect repellent application. DEET (2.3%

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.

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.

Factors influencing uncertainties of in vivo bone lead measurement using a (109)Cd K X-ray fluorescence clover leaf geometry detector system.

A (109)Cd K X-ray fluorescence (KXRF) measurement system consisting of four detectors in clover-leaf geometry is a non-invasive, low-radiation-dose method of measuring bone lead concentration. Its high precision in estimating the bone lead content makes it a promising tool for the determination of the low levels of lead currently found in the general population. After developing the clover-leaf geometry system, the system was used for the first time in a major survey in 2008 to measure the lead levels of 497 smelter employees (an occupationally exposed group with high lead levels). Since the delivered effective dose of the bone lead system in clover-leaf geometry is small (on the order of nSv), the technique can be used to measure the bone lead of sensitive populations such as the elderly and children. This detector system was used from 2009 to 2011, in a pilot study that measured the bone lead concentration of 263 environmentally exposed individuals (termed the EG group) residing in Toronto, Ontario, Canada. In this paper, the factors that influence uncertainties in lead content in tibia (cortical bone) and calcaneus (trabecular bone) are discussed based on gender, age, and body mass index (BMI) by using analysis of variance (ANOVA) and multiple linear regression models. Results from the two study groups (the EG group versus the occupationally exposed smelter employees) are compared where appropriate (i.e. for males older than 20). Results from univariate analyses showed that females have higher tibia uncertainty compared to males. We observed significant differences for both calcaneus and tibia uncertainty measures (p < 0.0005) among different age groups, where the uncertainties were highest in the lowest age group (<11 years). Lastly, and perhaps most significantly, we found that the product of source activity and measurement time influenced the precision of measurements greatly, and that this factor alone could account for the higher uncertainties observed for the male cohort of the EG group versus the smelter employees.

Thyroid hormone-regulated gene expression in juvenile mouse liver: identification of thyroid response elements using microarray profiling and in silico analyses.

BACKGROUND: Disruption of thyroid hormone signalling can alter growth, development and energy metabolism. Thyroid hormones exert their effects through interactions with thyroid receptors that directly bind thyroid response elements and can alter transcriptional activity of target genes. The effects of short-term thyroid hormone perturbation on hepatic mRNA transcription in juvenile mice were evaluated, with the goal of identifying genes containing active thyroid response elements. Thyroid hormone disruption was induced from postnatal day 12 to 15 by adding goitrogens to dams' drinking water (hypothyroid). A subgroup of thyroid hormone-disrupted pups received intraperitoneal injections of replacement thyroid hormones four hours prior to sacrifice (replacement). An additional group received only thyroid hormones four hours prior to sacrifice (hyperthyroid). Hepatic mRNA was extracted and hybridized to Agilent mouse microarrays. RESULTS: Transcriptional profiling enabled the identification of 28 genes that appeared to be under direct thyroid hormone-regulation. The regulatory regions of the genome adjacent to these genes were examined for half-site sequences that resemble known thyroid response elements. A bioinformatics search identified 33 thyroid response elements in the promoter regions of 13 different genes thought to be directly regulated by thyroid hormones. Thyroid response elements found in the promoter regions of Tor1a, 2310003H01Rik, Hect3d and Slc25a45 were further validated by confirming that the thyroid receptor is associated with these sequences in vivo and that it can bind directly to these sequences in vitro. Three different arrangements of thyroid response elements were identified. Some of these thyroid response elements were located far up-stream (> 7 kb) of the transcription start site of the regulated gene. CONCLUSIONS: Transcriptional profiling of thyroid hormone disrupted animals coupled with a novel bioinformatics search revealed new thyroid response elements associated with genes previously unknown to be responsive to thyroid hormone. The work provides insight into thyroid response element sequence motif characteristics.

Lack of change in microRNA expression in adult mouse liver following treatment with benzo(a)pyrene despite robust mRNA transcriptional response.

Benzo(a)pyrene (BaP) is a mutagenic and carcinogenic environmental contaminant. Metabolic activation of BaP is required for it to exert its mutagenic effects. Metabolism occurs via BaP interaction with the aryl hydrocarbon receptor (AHR) resulting in induction of phase 1 enzymes. Exposure to BaP is expected to cause differential regulation of AHR-responsive genes as well as pathways responding to DNA damage induced by its metabolites. MicroRNAs (miRNAs) are short non-coding molecules that control mRNA levels and protein translation. MiRNA regulation may also be affected by chemical insult. Here we investigate the correlation between hepatic mRNA and miRNA response to BaP in vivo. Mature male mice were orally exposed to 3 daily doses of 150mg/kg BaP. DNA microarrays were used to profile gene and miRNA expression in the liver 4 and 24h following the final dose. Despite widespread changes in gene expression (>400 genes) in pathways consistent with the known effects of BaP, we found no changes in miRNA. This was confirmed on two microarray platforms and by qRT-PCR. Analysis of positive controls (2 distinct reference pools) indicated that the Agilent technology could identify differences in miRNA. The effects of sample storage at -80°C were also compared. We found little effect of prolonged freezing on the technical correlation between samples or on differential expression. Our results are consistent with the lack of response of miRNA in rodent liver to dioxin, another potent AHR-agonist. We conclude that hepatic miRNA in vivo is not directly responsive to BaP exposure.