Alaska Native smokers and smokeless tobacco users with slower CYP2A6 activity have lower tobacco consumption, lower tobacco-specific nitrosamine exposure and lower tobacco-specific nitrosamine bioactivation.

Nicotine, the psychoactive ingredient in tobacco, is metabolically inactivated by CYP2A6 to cotinine. CYP2A6 also activates procarcinogenic tobacco-specific nitrosamines (TSNA). Genetic variation in CYP2A6 is known to alter smoking quantity and lung cancer risk in heavy smokers. Our objective was to investigate how CYP2A6 activity influences tobacco consumption and procarcinogen levels in light smokers and smokeless tobacco users. Cigarette smokers (n = 141), commercial smokeless tobacco users (n = 73) and iqmik users (n = 20) were recruited in a cross-sectional study of Alaska Native people. The participants' CYP2A6 activity was measured by both endophenotype and genotype, and their tobacco and procarcinogen exposure biomarker levels were also measured. Smokers, smokeless tobacco users and iqmik users with lower CYP2A6 activity had lower urinary total nicotine equivalents (TNE) and (methylnitrosamino)-1-(3)pyridyl-1-butanol (NNAL) levels (a biomarker of TSNA exposure). Levels of N-nitrosonornicotine (NNN), a TSNA metabolically bioactivated by CYP2A6, were higher in smokers with lower CYP2A6 activities. Light smokers and smokeless tobacco users with lower CYP2A6 activity reduce their tobacco consumption in ways (e.g. inhaling less deeply) that are not reflected by self-report indicators. Tobacco users with lower CYP2A6 activity are exposed to lower procarcinogen levels (lower NNAL levels) and have lower procarcinogen bioactivation (as indicated by the higher urinary NNN levels suggesting reduced clearance), which is consistent with a lower risk of developing smoking-related cancers. This study demonstrates the importance of CYP2A6 in the regulation of tobacco consumption behaviors, procarcinogen exposure and metabolism in both light smokers and smokeless tobacco users.

A multi-pathway exposure assessment for polycyclic aromatic hydrocarbons among residents in the Athabasca oil sands region, Canada.

Due to increasing emissions from ongoing development of the oil sands in Northern Alberta, Canada, there is concern that local residents and organisms are experiencing elevated exposures to hazardous contaminants. We modified an existing human bioaccumulation model (ACC-Human) to represent the local food chain in the Athabasca oil sands region (AOSR), the focus of oil sands development in Alberta. We used the model to assess the potential exposure to three polycyclic aromatic hydrocarbons (PAHs) among local residents that have a high intake of locally sourced traditional foods. To place these estimates into context, we complemented them with estimated PAH intake through market foods and smoking. Our approach was able to produce realistic body burdens of the PAHs in aquatic and terrestrial wildlife and in humans, both in magnitude and with respect to the relative difference between smokers and non-smokers. Over the model simulation period (1967-2009), market food was the dominant dietary exposure route for phenanthrene and pyrene, while local food, and in particular local fish, dominated the intake of benzo[a]pyrene. Exposure to benzo[a]pyrene therefore was also predicted to increase over time in concert with expanding oil sands operations. Those smoking at the average rate of Northern Albertans take in an additional amount of all three PAHs that is at least as large as dietary intake. Estimated daily intake rates are below toxicological reference thresholds for all three PAHs. However, daily intake of BaP in adults is only ∼20 fold below those thresholds and is predicted to increase. Key uncertainties in the assessment included the effect of food preparation on the PAH content in food (e.g., smoking of fish), the limited availability of market food contamination data specific to Canada, and the PAH content of the vapor phase of first-hand cigarette smoke. Considering the satisfactory model evaluation, ACC-Human AOSR should be suited to making predictions of future contaminant exposure based on development scenarios in the AOSR or in response to potential emission reduction efforts. It should also be applicable to other organic contaminants of concern released by oil sands operations.

Mixture effect assessment applying in vitro bioassays to in-tissue silicone extracts of traditional foods prepared from beluga whale blubber.

We complement an earlier study on the nutrient and environmental contaminant levels in Arctic beluga whale traditional foods by mixture effect assessment using in vitro bioassays. Mixtures were extracted by in-tissue sampling of raw blubber and several traditional food preparations including Muktuk and Uqsuq using silicone (polydimethylsiloxane, PDMS) as sampler. PDMS extracts persistent and degradable neutral organic chemicals of a wide range of hydrophobicity with defined lipid-PDMS partition ratios. The solvent extracts of PDMS were dosed in various reporter gene assays based on human cell lines. Cytotoxicity was consistent across all cell lines and was a good indicator of overall chemical burden. No hormone-like effects on the estrogen receptor, the progesterone receptor and the glucocorticoid receptor were observed but a few samples activated the androgen receptor, albeit with low potency. The peroxisome-proliferator activated receptor (PPARγ) was the most sensitive endpoint followed by activation of oxidative stress response and activation of the arylhydrocarbon (AhR) receptor. The detected pollutants only explained a small fraction of the experimental mixture effects, indicating additional bioactive pollutants. The effect levels of the extracted mixtures were higher than those observed in blubber extracts of dugongs living off the shore of Australia. Roasting over an open fire or food preparation near a smokehouse led to increased PAH levels that were reflected in increased oxidative stress response and activation of the AhR. So far in vitro assays have only been used to quantify persistent dioxin-like chemicals in food and feed but this pilot study demonstrates a much broader potential for food safety evaluations complementing chemical analytical monitoring.

CYP2A6 and CYP2B6 genetic variation and its association with nicotine metabolism in South Western Alaska Native people.

OBJECTIVES: Alaska Native (AN) people have a high prevalence of tobacco use and associated morbidity and mortality when compared with the general USA population. Variations in the CYP2A6 and CYP2B6 genes, encoding enzymes responsible for nicotine metabolic inactivation and procarcinogen activation, have not been characterized in AN and may contribute toward the increased risk. METHODS: AN people (n=400) residing in the Bristol Bay region of South Western Alaska were recruited for a cross-sectional study on tobacco use. They were genotyped for CYP2A6*1X2A, *1X2B, *1B, *2, *4, *7, *8, *9, *10, *12, *17, *35 and CYP2B6*4, *6, *9 and provided plasma and urine samples for the measurement of nicotine and metabolites. RESULTS: CYP2A6 and CYP2B6 variant frequencies among the AN Yupik people (n=361) were significantly different from those in other ethnicities. Nicotine metabolism [as measured by the plasma and urinary ratio of metabolites trans-3'-hydroxycotinine to cotinine (3HC/COT)] was significantly associated with CYP2A6 (P<0.001), but not CYP2B6 genotype (P=0.95) when controlling for known covariates. It was noteworthy that the plasma 3HC/COT ratios were high in the entire Yupik people, and among the Yupik CYP2A6 wild-type participants, they were substantially higher than those in previously characterized racial/ethnic groups (P<0.001 vs. Caucasians and African Americans). CONCLUSION: Yupik AN people have a unique CYP2A6 genetic profile that associated strongly with in-vivo nicotine metabolism. More rapid CYP2A6-mediated nicotine and nitrosamine metabolism in the Yupik people may modulate the risk of tobacco-related diseases.

Effects of preparation on nutrient and environmental contaminant levels in Arctic beluga whale (Delphinapterus leucas) traditional foods.

For Canadian Arctic indigenous populations, marine mammal (MM) traditional foods (TFs) represent sources of both important nutrients and hazardous environmental contaminants. Food preparation is known to impact the nutrient and environmental contaminant content of processed items, yet the impacts of preparation on indigenous Arctic MM TFs remain poorly characterized. In order to determine how the various processes involved in preparing beluga blubber TFs affect their levels of nutrients and environmental contaminants, we collected blubber samples from 2 male beluga whales, aged 24 and 37 years, captured during the 2014 summer hunting season in Tuktoyaktuk, Northwest Territories, and processed them according to local TF preparation methods. We measured the levels of select nutrients [selenium (Se), polyunsaturated fatty acids (PUFAs)] and contaminants [organochlorine pesticides, perfluoroalkyl and polyfluoroalkyl substances (PFASs), polybrominated diphenyl ethers, polychlorinated biphenyls, polycyclic aromatic hydrocarbons (PAHs), mercury (Hg)] in raw and prepared (boiled, roasted, aged) beluga blubber TFs. The impacts of beluga blubber TF preparation methods on nutrient and environmental contaminant levels were inconsistent, as the majority of processes either did not appear to influence concentrations or affected the two belugas differently. However, roasting and ageing beluga blubber consistently impacted certain compounds: roasting blubber increased concentrations of hydrophilic substances (Se and certain PFASs) through solvent depletion and deposited PAHs from cookfire smoke. The solid-liquid phase separation involved in ageing blubber depleted hydrophilic elements (Se, Hg) and some ionogenic PFASs from the lipid-rich liquid oil phase, while PUFA levels appeared to increase, and hydrophobic persistent organic pollutants were retained. Ageing blubber adjacent to in-use smokehouses also resulted in considerable PAH deposition to processed samples. Our findings demonstrated that contaminant concentration differences were greater between the two sets of whale samples, based on age differences, than they were within each set of whale samples, due to variable preparation methods. When considering means to minimize human contaminant exposure while maximizing nutrient intake, consumption of aged liquid from younger male whales would be preferred, based on possible PUFA enhancement and selective depletion of hydrophilic environmental contaminants in this food item.

Balancing the benefits and costs of traditional food substitution by indigenous Arctic women of childbearing age: Impacts on persistent organic pollutant, mercury, and nutrient intakes.

For indigenous Arctic Canadians, traditional food consumption represents a key source of nutrients and environmental contaminants. Particularly, ingestion of marine mammal blubber and meat may lead to persistent organic pollutant levels and mercury intakes that exceed regulatory thresholds for sensitive populations. We investigated whether temporary adjustments to the consumption of traditional food derived from marine mammals appreciably impacted contaminant exposure and nutrient intakes among indigenous women of childbearing age. Such adjustments can be motivated by the desire to lower contaminant exposure or to increase nutrition, or by the diminishing availability of other traditional food sources. We combined the contaminant fate and transport model GloboPOP with the food chain bioaccumulation model ACC-Human Arctic to simulate polychlorinated biphenyl exposures in female 2007-08 Inuit Health Survey participants. We also calculated daily mercury and nutrient intake rates. Our results suggest that a temporary decrease in marine mammal consumption is largely ineffective at reducing exposure to polychlorinated biphenyls, because of their long elimination half-lives. In contrast, substitution of marine mammals was highly efficient at reducing mercury intake, but also appreciably lowered intakes of iron, manganese, selenium, and ω-3 polyunsaturated fatty acids. The impact of increasing intake of traditional food derived from marine mammals during childbearing age greatly depended on baseline consumption rates; replacement is ill-advised for those who already consume a lot of traditional food due to greater polychlorinated biphenyl and mercury exposures, while replacement was potentially beneficial for those with very limited marine mammal consumption due to increased nutrient intakes. Our calculations primarily suggest that considering baseline traditional food intake rates is critical to devising reproductive dietary adjustment strategies that maximize nutrient intake while minimizing environmental contaminant exposure.

Deterministic modeling of the exposure of individual participants in the National Health and Nutrition Examination Survey (NHANES) to polychlorinated biphenyls.

A population's exposure to persistent organic pollutants, e.g., polychlorinated biphenyls (PCBs), is typically assessed through national biomonitoring programs, such as the United States National Health and Nutrition Examination Survey (NHANES). To complement statistical methods, we use a deterministic modeling approach to establish mechanistic links between human contaminant concentrations and factors (e.g. age, diet, lipid mass) deemed responsible for the often considerable variability in these concentrations. Lifetime exposures to four PCB congeners in 6128 participants from NHANES 1999-2004 are simulated using the ACC-Human model supplied with individualized input parameters obtained from NHANES questionnaires (e.g., birth year, sex, body mass index, dietary composition, reproductive behavior). Modeled and measured geometric mean PCB-153 concentrations in NHANES participants of 13.3 and 22.0 ng g-1 lipid, respectively, agree remarkably well, although lower model-measurement agreement for air, water, and food suggests that this is partially due to fortuitous error cancellation. The model also reproduces trends in the measured data with key factors such as age, parity and sex. On an individual level, 62% of all modeled concentrations are within a factor of three of their corresponding measured values (Spearman rs = 0.44). However, the model attributes more of the inter-individual variability to differences in dietary lipid intake than is indicated by the measured data. While the model succeeds in predicting levels and trends on the population level, the accuracy of individual-specific predictions would need to be improved for refined exposure characterization in epidemiological studies.

Mechanistic polychlorinated biphenyl exposure modeling of mothers in the Canadian Arctic: the challenge of reliably establishing dietary composition.

BACKGROUND: Traditional food (TF) consumption represents the main route of persistent organic pollutant (POP) exposure for indigenous Arctic Canadians. Ongoing dietary transitions away from TFs and toward imported foods (IFs) may contribute to decreasing POP exposures observed in these groups. METHODS: To explore this issue, we combined the global fate and transport model GloboPOP and the human food chain bioaccumulation model ACC-Human Arctic to simulate polychlorinated biphenyl (PCB) exposure in two indigenous Arctic Canadian communities from the Inuvik region, Northwest Territories and Baffin region, Nunavut. Using dietary survey information from initial (1996-98) and follow-up (2005-07) biomonitoring campaigns in Inuvik and Baffin, we simulated PCB exposures (PCB-118, -138, -153, and -180) for each individual study participant and also whole study populations. RESULTS: TF intake rates, particularly of marine mammals (MMs), were the most important predictors of modeled PCB exposure, while TF consumption did not associate consistently with measured PCB exposures. Further, reported mean TF intake increased from baseline to follow-up in both Inuvik (from 8 to 183gd(-1)) and Baffin (from 60 to 134gd(-1)), opposing both the expected dietary transition direction and the observed decrease in human PCB exposures in these communities (ΣPCB Inuvik: from 43 to 29ngglipid(-1), ΣPCB Baffin: from 213 to 82ngglipid(-1)). However dietary questionnaire data are frequently subject to numerous biases (e.g., recall, recency, confirmation), and thus casts doubt on the usefulness of these data. CONCLUSIONS: Ultimately, our model's capability to reproduce historic PCB exposure data in these two groups was highly sensitive to TF intake, further underscoring the importance of accurate TF consumption reporting, and clarification of the role of dietary transitions in future POP biomonitoring of indigenous Arctic populations.

Clarifying relationships between persistent organic pollutant concentrations and age in wildlife biomonitoring: individuals, cross-sections, and the roles of lifespan and sex.

Relationships between persistent organic pollutant (POP) levels and age in wildlife biomonitoring are often interpreted as changes in contaminant burden as organisms age. However, cross-sectional body burden-age trends (CBATs) obtained from biomonitoring studies, which sample individuals of different ages at the same time, should not be confused with longitudinal body burden-age trends (LBATs) obtained by sampling the same individuals repeatedly through time. To clarify how CBATs and LBATs for wildlife species deviate from each other, and describe any impact of lifespan and sex, we used mechanistic bioaccumulation models to estimate historic longitudinal exposures of polar cod, ringed seals, beluga whales, and bowhead whales to polychlorinated biphenyl congener 153. Cross-sectional body burden-age trends were then produced by sampling resultant LBATs of successive birth cohorts at specific time points. As found previously for humans, the year of sampling relative to the year of peak environmental contamination was a critical parameter in determining male CBAT shapes. However, a similar cohort effect was not apparent for reproductive females because efficient POP loss through lactation prevented their lipids from retaining a memory of past exposure levels. Thus, lactation loss was not only responsible for the large differences between the CBATs of males and females of the same species, but also the lack of female CBAT variability through time. Cross-sectional body burden-age trend shapes varied little between species by lifespan, as long as equivalent age scales were used. However, lifespan relative to the timescale of environmental contaminant level changes did determine the extent to which CBATs resembled LBATs for males. We suggest that accounting for birth cohort and sex effects is essential when interpreting age trends in POP biomonitoring studies of long-lived species.

Evaluating the effectiveness of fish consumption advisories: modeling prenatal, postnatal, and childhood exposures to persistent organic pollutants.

BACKGROUND: Because human exposure to persistent organic pollutants (POPs) occurs mainly through ingestion of contaminated food, regulatory bodies issue dietary consumption advisories to describe safe intake levels for food items of concern, particularly fish. OBJECTIVES: Our study goal was to estimate the effectiveness of fish consumption advisories in reducing exposure of infants and children to POPs. METHODS: We used the time-variant mechanistic model CoZMoMAN to estimate and compare prenatal, postnatal, and childhood exposure to polychlorinated biphenyl congener PCB-153 under different scenarios of maternal guideline adherence for both hypothetical constant and realistic time-variant chemical emissions. The scenarios differed in terms of length of compliance (1 vs. 5 years), extent of fish substitution (all vs. half), and replacement diet (uncontaminated produce vs. beef). We also estimated potential exposure reductions for a range of theoretical chemicals to explore how guideline effectiveness varies with a chemical's partitioning and degradation properties. RESULTS: When assuming realistic time periods of advisory compliance, our findings suggest that temporarily eliminating or reducing maternal fish consumption is largely ineffective in reducing pre- and postnatal exposure to substances with long elimination half-lives in humans, especially during periods of decreasing environmental emissions. Substituting fish with beef may actually result in higher exposure to certain groups of environmental contaminants. On the other hand, advisories may be highly effective in reducing exposure to substances with elimination half-lives in humans shorter than the length of compliance. CONCLUSIONS: Our model estimates suggest that fish consumption advisories are unlikely to be effective in reducing prenatal, postnatal, and childhood exposures to compounds with long elimination half-lives in humans.