Biomonitoring Equivalents Research Articles

Human biomonitoring of metals in adults living near a waste-to-energy incinerator in ante-operam phase: Focus on reference values and health-based assessments

The human biomonitoring (HBM) of metals is a part of the ongoing project SPoTT for the longitudinal health surveillance of the population living near a waste-to-energy (WTE) incinerator (Turin, Italy). The HBM of metals in the SPoTT population aimed to evaluate: i) reference values (RVs) before the WTE incinerator started operation; ii) differences in exposure by variables; iii) variations respect to other HBM studies; iv) exposure that exceeds the available health-based benchmarks as the Biomonitoring Equivalents (BEs) for urine Cd and Human Biomonitoring (HBM-I and HBM-II) values for urine Hg, Tl, and blood Pb; v) risk assessment by generating hazard quotients (HQs) for the single metal and hazard index (HI) for the co-occurrence of metals. Eighteen metals in urine and Pb in blood were determined by sector field inductively coupled plasma mass spectrometry. Metal concentrations were comparable with RVs reported in other countries, except for slightly higher As, Be, Ir, Pd, Pt, Rh, and Tl levels. Smoking was associated with Cd; age with Pb; drinking bottled water with As and Cd; consumption of fish with As and Hg; amalgams with Hg and Sn; dental restorations with Pd and Pt; use of jewelry with Co and Rh, and piercing with Ni. While HQs for urine Cd, Hg, Tl and blood Pb suggested that adverse effects were unlikely, the HQ value raised the question of whether additive interactions of these metals could produce health concern. The obtained HBM data can be an early warning for accumulations of metals and identification of subgroups at risk.

Biomonitoring Equivalents for molybdenum

Molybdenum is an essential trace element for mammalian, plant, and other animal systems. The Institute of Medicine (IOM) has established an Estimated Average Requirement (EAR) to assure sufficient molybdenum intakes for human populations; however excessive exposures can cause toxicity. As a result, several agencies have established exposure guidance values to protect against molybdenum toxicity, including a Reference Dose (RfD), Tolerable Daily Intake (TDI) and a Tolerable Upper Intake Level (UL). Biomonitoring for molybdenum in blood or urine in the general population is being conducted by the Canadian Health Measures Survey (CHMS) and the U.S. National Health and Nutrition Examination Survey (NHANES). Using pharmacokinetic data from controlled human dosing studies, Biomonitoring Equivalents (BEs) were calculated for molybdenum in plasma, whole blood, and urine associated with exposure guidance values set to protect against both nutritional deficits and toxicity. The BEEAR values in plasma, whole blood and urine are 0.5, 0.45 and 22 μg/L, respectively. The BEs associated with toxicity range from 0.9 to 31 μg/L in plasma, 0.8–28 μg/L in whole blood and 200–7500 μg/L in urine. These values can be used to interpret molybdenum biomonitoring data from a nutritional and toxicity perspective.

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.

California biomonitoring data: Comparison to NHANES and interpretation in a risk assessment context

The California Environmental Biomonitoring Program (also known as Biomonitoring California) has been generating human biomonitoring data and releasing it via their website. The current Biomonitoring California program is a collection of smaller studies, targeting specific populations (e.g., fire fighters, breast cancer patients and controls, etc.). In this paper we compare the results from Biomonitoring California with those from the US National Health and Nutrition Examination Survey (NHANES). We also compare California's results with Biomonitoring Equivalents (BEs) for those compounds for which BEs exist. In general, the results from California are consistent with the biomonitoring levels found across the US via NHANES. A few notable exceptions are levels of flame retardants amongst fire fighters in California, which are higher than observed in NHANES and some persistent organic chemicals amongst a study of breast cancer patients and controls in California which are higher than in the overall adult population in NHANES. The higher levels amongst fire fighters may be a result of fire fighters being exposed to higher levels of flame retardants while fighting fires. The higher levels of the persistent organics amongst breast cancer patients is likely due to this population being older than the mean age in NHANES. Comparisons to BEs indicate that biomonitoring levels in California are all consistently below levels of concern as established by regulatory agencies.

Implementing a framework for integrating toxicokinetics into human health risk assessment for agrochemicals

A strategic and comprehensive program in which toxicokinetic (TK) measurements are made for all agrochemicals undergoing toxicity testing (both new compounds and compounds already registered for use) is described. This approach provides the data to more accurately assess the toxicokinetics of agrochemicals and their metabolites in laboratory animals and humans. Having this knowledge provides the ability to conduct more insightful toxicity studies, refine and interpret exposure assessments and reduce uncertainty in risk assessments. By developing a better understanding of TK across species, including humans via in vitro metabolism studies, any differences across species in TK can be identified early and the most relevant species can be selected for toxicity tests. It also provides the ability to identify any non-linearities in TK as a function of dose, which in turn can be used to identify a kinetically derived maximum dose (KMD) and avoid dosing inappropriately outside of the kinetic linear range. Measuring TK in key life stages also helps to identify changes in ADME parameters from in utero to adults. A robust TK database can also be used to set internal concentration based “Reference Concentrations” and Biomonitoring Equivalents (BE), and support selection of Chemical Specific Adjustment Factors (CSAF). All of these factors support the reduction of uncertainty throughout the entire risk assessment process. This paper outlines how a TK research strategy can be integrated into new agrochemical toxicity testing programs, together with a proposed Framework for future use.

Deriving Biomonitoring Equivalents for selected E- and P-series glycol ethers for public health risk assessment.

Glycol ethers are a widely used class of solvents that may lead to both workplace and general population exposures. Biomonitoring studies are available that have quantified glycol ethers or their metabolites in blood and/or urine amongst exposed populations. These biomonitoring levels indicate exposures to the glycol ethers, but do not by themselves indicate a health hazard risk. Biomonitoring Equivalents (BEs) have been created to provide the ability to interpret human biomonitoring data in a public health risk context. The BE is defined as the concentration of a chemical or metabolite in a biological fluid (blood or urine) that is consistent with exposures at a regulatory derived safe exposure limit, such as a tolerable daily intake (TDI). In this exercise, we derived BEs for general population exposures for selected E- and P-series glycol ethers based on their respective derived no effect levels (DNELs). Selected DNELs have been derived as part of respective Registration, Evaluation, Authorisation and Regulation of Chemicals (REACh) regulation dossiers in the EU. The BEs derived here are unique in the sense that they are the first BEs derived for urinary excretion of compounds following inhalation exposures. The urinary mass excretion fractions (Fue) of the acetic acid metabolites for the E-series GEs range from approximately 0.2 to 0.7. The Fues for the excretion of the parent P-series GEs range from approximately 0.1 to 0.2, with the exception of propylene glycol methyl ether and its acetate (Fue = 0.004). Despite the narrow range of Fues, the BEs exhibit a larger range, resulting from the larger range in DNELs across GEs. The BEs derived here can be used to interpret human biomonitoring data for inhalation exposures to GEs amongst the general population.

Human plasma concentrations of cytochrome P450 probes extrapolated from pharmacokinetics in cynomolgus monkeys using physiologically based pharmacokinetic modeling

1. Cynomolgus monkeys are widely used in preclinical studies as non-human primate species. Pharmacokinetics of human cytochrome P450 probes determined in cynomolgus monkeys after single oral or intravenous administrations were extrapolated to give human plasma concentrations.2. Plasma concentrations of slowly eliminated caffeine and R-/S-warfarin and rapidly eliminated omeprazole and midazolam previously observed in cynomolgus monkeys were scaled to human oral biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Results of the simplified human PBPK models were consistent with reported experimental PK data in humans or with values simulated by a fully constructed population-based simulator (Simcyp).3. Oral administrations of metoprolol and dextromethorphan (human P450 2D probes) in monkeys reportedly yielded plasma concentrations similar to their quantitative detection limits. Consequently, ratios of in vitro hepatic intrinsic clearances of metoprolol and dextromethorphan determined in monkeys and humans were used with simplified PBPK models to extrapolate intravenous PK in monkeys to oral PK in humans.4. These results suggest that cynomolgus monkeys, despite their rapid clearance of some human P450 substrates, could be a suitable model for humans, especially when used in conjunction with simple PBPK models.

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.

Human biofluid concentrations of mono(2-ethylhexyl)phthalate extrapolated from pharmacokinetics in chimeric mice with humanized liver administered with di(2-ethylhexyl)phthalate and physiologically based pharmacokinetic modeling

Di(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant in male rodents. The aim of the current study was to extrapolate the pharmacokinetics and toxicokinetics of mono(2-ethylhexyl)phthalate (MEHP, a primary metabolite of DEHP) in humans by using data from oral administration of DEHP to chimeric mice transplanted with human hepatocytes. MEHP and its glucuronide were detected in plasma from control mice and chimeric mice after single oral doses of 250mg DEHP/kg body weight. Biphasic plasma concentration–time curves of MEHP and its glucuronide were seen only in control mice. MEHP and its glucuronide were extensively excreted in urine within 24h in mice with humanized liver. In contrast, fecal excretion levels of MEHP glucuronide were high in control mice compared with those with humanized liver. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated urine MEHP concentrations in humans were consistent with reported concentrations. This research illustrates how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of pharmacokinetics or toxicokinetics of the primary or secondary metabolites of DEHP.

Review of the state of the art of human biomonitoring for chemical substances and its application to human exposure assessment for food safety

Review of the state of the art of human biomonitoring for chemical substances and its application to human exposure assessment for food safety

Exposure to arsenic in relation with DNA damage in adolescents of the 3rd Flemish environment and health study (2012-2014)

Exposure to arsenic in relation with DNA damage in adolescents of the 3rd Flemish environment and health study (2012-2014)

Evaluation of Biomonitoring Equivalents for Benzene Risk Assessment: an Environmental-Wide Association Study Approach

A biomonitoring equivalent (BE) is the concentration of a chemical or its metabolite in a biological matrix. The BE is estimated from an existing exposure guidance value such as a reference dose (RfD). An environmental-wide association study (EWAS) provides an epidemiologic screening tool to simultaneously evaluate multiple health outcomes for potential association with an exposure. We evaluated over 120 health outcomes, including self-reported medical and disease conditions and blood chemistry parameters, for potential associations with blood benzene level. The study population included adults who participated in the 2003-04 and 2005-06 waves of the National Health and Nutrition Examination Survey. Logistic regression models of benzene classified as above or below the BE were adjusted for age, sex, race, smoking, and socioeconomic status. Odds ratios (OR) estimated the association between each health outcome for an elevated BE relative to a concentration below the BE. More than 1,300 adults with blood benzene concentration were included. The proportion with a blood benzene level exceeding the BE value was 12%. Blood benzene level was positively associated with an elevated serum cotinine level indicative of current cigarette smoking (OR=1.03, p<0.01). Among current smokers, having a blood benzene level above the BE was associated with elevated white blood cell count (OR=1.1, p<0.05), hemoglobin (OR=1.3, p<0.01), hematocrit (OR=1.1, p=0.01), and albumin (OR=2.3, p=0.03), and decreased blood urea nitrogen (OR=0.9, p<0.01) and alpha-carotene (OR=0.8, p<0.01). We observed significant associations between elevated blood benzene level and several clinical biochemistry parameters. Biomarker concentrations expressed as BE values allow for evaluation of health risks using population-based biomonitoring data. The EWAS approach can assess the distribution of risks for a range of health outcomes in a general population for exposure levels relative to an RfD.

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.

Pharmacokinetics and effects on serum cholinesterase activities of organophosphorus pesticides acephate and chlorpyrifos in chimeric mice transplanted with human hepatocytes

Organophosphorus pesticides acephate and chlorpyrifos in foods have potential to impact human health. The aim of the current study was to investigate the pharmacokinetics of acephate and chlorpyrifos orally administered at lowest-observed-adverse-effect-level doses in chimeric mice transplanted with human hepatocytes. Absorbed acephate and its metabolite methamidophos were detected in serum from wild type mice and chimeric mice orally administered 150mg/kg. Approximately 70% inhibition of cholinesterase was evident in plasma of chimeric mice with humanized liver (which have higher serum cholinesterase activities than wild type mice) 1day after oral administrations of acephate. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated plasma concentrations of acephate and chlorpyrifos in humans were consistent with reported concentrations. Acephate cleared similarly in humans and chimeric mice but accidental/incidental overdose levels of chlorpyrifos cleared (dependent on liver metabolism) more slowly from plasma in humans than it did in mice. The data presented here illustrate how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of toxicological potential of organophosphorus pesticides.

Biomonitoring Equivalents for selenium

Selenium is an essential nutrient for human health with a narrow range between essentiality and toxicity. Selenium is incorporated into several proteins that perform important functions in the body. With insufficient selenium intake, the most notable effect is Keshan disease, an endemic cardiomyopathy in children. Conversely, excessive selenium intake can result in selenosis, manifested as brittle nails and hair and gastro-intestinal disorders. As such, guidance values have been established to protect against both insufficient and excessive selenium exposures. Dietary Reference Intakes (DRIs) have been established as standard reference values for nutritional adequacy in North America. To protect against selenosis resulting from exposure to excessive amounts of selenium, several government and non-governmental agencies have established a range of guidance values. Exposure to selenium is primarily through the diet, but monitoring selenium intake is difficult. Biomonitoring is a useful means of assessing and monitoring selenium status for both insufficient and excessive exposures. However, to be able to interpret selenium biomonitoring data, levels associated with both DRIs and toxicity guidance values are required. Biomonitoring Equivalents (BEs) were developed for selenium in whole blood, plasma and urine. The BEs associated with assuring adequate selenium intake (Estimated Average Requirements – EAR) are 100, 80 and 10μg/L in whole blood, plasma and urine, respectively. The BEs associated with protection against selenosis range from 400 to 480μg/L in whole blood, 180–230μg/L in plasma, and 90–110μg/L in urine. These BE values can be used by both regulatory agencies and public health officials to interpret selenium biomonitoring data in a health risk context.

Human plasma concentrations of herbicidal carbamate molinate extrapolated from the pharmacokinetics established in in vivo experiments with chimeric mice with humanized liver and physiologically based pharmacokinetic modeling

To predict concentrations in humans of the herbicidal carbamate molinate, used exclusively in rice cultivation, a forward dosimetry approach was carried out using data from lowest-observed-adverse-effect-level doses orally administered to rats, wild type mice, and chimeric mice with humanized liver and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated hydroxylation of molinate, but rat livers additionally produced molinate sulfoxide and an unidentified metabolite. Adjusted animal biomonitoring equivalents for molinate and its primary sulfoxide from animal studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. The slower disposition of molinate and accumulation of molinate sulfoxide in humans were estimated by modeling after single and multiple doses compared with elimination in rodents. The results from simplified PBPK modeling in combination with chimeric mice with humanized liver suggest that ratios of estimated parameters of molinate sulfoxide exposure in humans to those in rats were three times as many as general safety factor of 10 for species difference in toxicokinetics. Thus, careful regulatory decision is needed when evaluating the human risk resulting from exposure to low doses of molinate and related carbamates based on data obtained from rats.

Plasma concentrations of melengestrol acetate in humans extrapolated from the pharmacokinetics established in in vivo experiments with rats and chimeric mice with humanized liver and physiologically based pharmacokinetic modeling

Some synthetic chemicals are suspected to be responsible for adverse effects on endocrine function. Sex hormones administered to farm animals are of particular interest because of their regulatory role in developmental processes. To predict concentrations in humans of the synthetic growth promoter melengestrol acetate (17α-acetoxy-6-methyl-16-methylenepregna-4,6-diene-3,20-dione), a forward dosimetry approach was carried out using data from no-observed-adverse-effect-level doses orally administered to mice or rats and from in vitro human and rodent experiments. Human liver microsomes preferentially mediated 2-hydroxylation of melengestrol acetate, but rodent livers produced additional unidentified hydroxymetabolites. Adjusted animal biomonitoring equivalents for melengestrol acetate from mouse and rat studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and human metabolic data with a simple physiologically based pharmacokinetic (PBPK) model. Melengestrol acetate elimination in humans was estimated to be slow compared with elimination in rodents. The disposition of melengestrol acetate in humans was evaluated using chimeric TK-NOG mice with humanized liver. The results suggest the usefulness of simplified PBPK modeling combined with in vitro and in vivo experiments and literature resources as well as a future interest in estimating by a full PBPK modeling using another bottom up system. This model may also be useful for risk evaluation and for simulating plasma concentrations resulting from exposure to low doses of melengestrol acetate and related compounds.

Evaluation of Biomonitoring Data from the CDC National Exposure Report in a Risk Assessment Context: Perspectives across Chemicals

Background: Biomonitoring data reported in the National Report on Human Exposure to Environmental Chemicals [NER; Centers for Disease Control and Prevention (2012)] provide information on the presence and concentrations of > 400 chemicals in human blood and urine. Biomonitoring Equivalents (BEs) and other risk assessment–based values now allow interpretation of these biomonitoring data in a public health risk context.Objectives: We compared the measured biomarker concentrations in the NER with BEs and similar risk assessment values to provide an across-chemical risk assessment perspective on the measured levels for approximately 130 analytes in the NER.Methods: We identified available risk assessment–based biomarker screening values, including BEs and Human Biomonitoring-I (HBM-I) values from the German Human Biomonitoring Commission. Geometric mean and 95th percentile population biomarker concentrations from the NER were compared to the available screening values to generate chemical-specific hazard quotients (HQs) or cancer risk estimates.Conclusions: Most analytes in the NER show HQ values of < 1; however, some (including acrylamide, dioxin-like chemicals, benzene, xylene, several metals, di-2(ethylhexyl)phthalate, and some legacy organochlorine pesticides) approach or exceed HQ values of 1 or cancer risks of > 1 × 10–4 at the geometric mean or 95th percentile, suggesting exposure levels may exceed published human health benchmarks. This analysis provides for the first time a means for examining population biomonitoring data for multiple environmental chemicals in the context of the risk assessments for those chemicals. The results of these comparisons can be used to focus more detailed chemical-specific examination of the data and inform priorities for chemical risk management and research.

2,4-D Exposure and risk assessment: Comparison of external dose and biomonitoring based approaches

Conventional chemical exposure assessment relies upon measurements or estimates of chemical concentrations in environmental media, food, or products, in combination with assumptions regarding contact rates, in order to estimate external doses (ppm in air) or intake rates of chemicals (e.g., mg/kg/day ingested). A risk assessment is conducted by comparing these external or intake dose estimates to appropriate (e.g., route-specific) exposure guidance values (e.g., Reference Dose or Reference Concentration) to assess whether exposures are exceeding levels of concern. Human biomonitoring, in which concentrations of chemicals are measured in blood or urine, is being increasingly used as an alternative or complementary exposure assessment. The Biomonitoring Equivalent, which is the translation of a Reference Dose to an equivalent concentration of a compound in blood or urine, provides a parallel means to interpret biomonitoring data in order to assess whether chemical-specific exposures exceed levels of concern. This manuscript presents a side-by-side comparison of the two approaches for assessing exposures and risks for a case study compound, 2,4-dichlorophenoxyacetic acid (2,4-D). The findings from this case study indicate that the external dose-based assessments result in estimates of exposure and resulting hazard quotients that are consistently several-fold higher than those based on biomonitoring data. These comparisons support a conclusion that exposure assessments conducted as part of the registration process for 2,4-D incorporate sufficiently conservative assumptions.

Cadmium exposure and tobacco consumption: Biomarkers and risk assessment

To investigate whether cadmium has an independent role in diseases associated with tobacco consumption, epidemiology data were reviewed, biomonitoring data were analyzed, and probabilistic risk assessment (PRA) was performed. Results from previous epidemiology studies have indicated that there are adverse health effects potentially in common between cadmium exposure and tobacco consumption. Analysis of publically available biomonitoring data showed that blood (B–Cd) and urine (U–Cd) cadmium were higher in cigarette smokers compared with smokeless tobacco (SLT) consumers, and B–Cd and U–Cd in SLT consumers were not significantly different than in non-consumers of tobacco. Comparison with previously established biomonitoring equivalent (BE) values indicated that B–Cd and U–Cd in the majority of these cigarette smokers and SLT consumers did not exceed the blood and urine BEs. Results of the PRA showed that the mean hazard estimate was below a generally accepted regulatory threshold for SLT consumers, but not for cigarette smokers. In total, this evaluation indicated that cadmium exposures in tobacco consumers differed by product category consumed; cadmium in tobacco may not be associated with tobacco consumption related diseases; if cadmium in tobacco contributes to tobacco consumption related diseases, differences in hazard and/or risk may exist by product category.