Human Variability in Susceptibility to Toxic Chemicals— A Preliminary Analysis of Pharmacokinetic Data from Normal Volunteers

The tenfold "uncertainty" factor traditionally used to guard against human interindividual differences in susceptibility to toxicity is not based on human observations. To begin to build a basis for quantifying an important component of overall variability in susceptibility to toxicity, a data base has been constructed of individual measurements of key pharmacokinetic parameters for specific substances (mostly drugs) in groups of at least five healthy adults. 72 of the 101 data sets studied were positively skewed, indicating that the distributions are generally closer to expectations for log-normal distributions than for normal distributions. Measurements of interindividual variability in elimination half-lives, maximal blood concentrations, and AUC (area under the curve of blood concentration by time) have median values of log10 geometric standard deviations in the range of 0.11-0.145. For the median chemical, therefore, a tenfold difference in these pharmacokinetic parameters would correspond to 7-9 standard deviations in populations of normal healthy adults. For one relatively lipophilic chemical, however, interindividual variability in maximal blood concentration and AUC was 0.4--implying that a tenfold difference would correspond to only about 2.5 standard deviations for those parameters in the human population. The parameters studied to date are only components of overall susceptibility to toxic agents, and do not include contributions from variability in exposure- and response-determining parameters. The current study also implicitly excludes most human interindividual variability from age and illness. When these other sources of variability are included in an overall analysis of variability in susceptibility, it is likely that a tenfold difference will correspond to fewer standard deviations in the overall population, and correspondingly greater numbers of people at risk of toxicity.     

Use of Markov Chain Monte Carlo Analysis with a Physiologically-Based Pharmacokinetic Model of Methylmercury to Estimate Exposures in U.S. Women of Childbearing Age

A Bayesian approach, implemented using Markov Chain Monte Carlo (MCMC) analysis, was applied with a physiologically‐based pharmacokinetic (PBPK) model of methylmercury (MeHg) to evaluate the variability of MeHg exposure in women of childbearing age in the U.S. population. The analysis made use of the newly available National Health and Nutrition Survey (NHANES) blood and hair mercury concentration data for women of age 16–49 years (sample size, 1,582). Bayesian analysis was performed to estimate the population variability in MeHg exposure (daily ingestion rate) implied by the variation in blood and hair concentrations of mercury in the NHANES database. The measured variability in the NHANES blood and hair data represents the result of a process that includes interindividual variation in exposure to MeHg and interindividual variation in the pharmacokinetics (distribution, clearance) of MeHg. The PBPK model includes a number of pharmacokinetic parameters (e.g., tissue volumes, partition coefficients, rate constants for metabolism and elimination) that can vary from individual to individual within the subpopulation of interest. Using MCMC analysis, it was possible to combine prior distributions of the PBPK model parameters with the NHANES blood and hair data, as well as with kinetic data from controlled human exposures to MeHg, to derive posterior distributions that refine the estimates of both the population exposure distribution and the pharmacokinetic parameters. In general, based on the populations surveyed by NHANES, the results of the MCMC analysis indicate that a small fraction, less than 1%, of the U.S. population of women of childbearing age may have mercury exposures greater than the EPA RfD for MeHg of 0.1 μg/kgg/day, and that there are few, if any, exposures greater than the ATSDR MRL of 0.3 μgg/kgg/day. The analysis also indicates that typical exposures may be greater than previously estimated from food consumption surveys, but that the variability in exposure within the population of U.S. women of childbearing age may be less than previously assumed.     

Variability in PAH-DNA Adduct Measurements in Peripheral Mononuclear Cells: Implications for Quantitative Cancer Risk Assessment

Biomarkers such as DNA adducts have significant potential to improve quantitative risk assessment by characterizing individual differences in metabolism of genotoxins and DNA repair and accounting for some of the factors that could affect interindividual variation in cancer risk. Inherent uncertainty in laboratory measurements and within-person variability of DNA adduct levels over time are putatively unrelated to cancer risk and should be subtracted from observed variation to better estimate interindividual variability of response to carcinogen exposure. A total of 41 volunteers, both smokers and nonsmokers, were asked to provide a peripheral blood sample every 3 weeks for several months in order to specifically assess intraindividual variability of polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels. The intraindividual variance in PAH-DNA adduct levels, together with measurement uncertainty (laboratory variability and unaccounted for differences in exposure), constituted roughly 30% of the overall variance. An estimated 70% of the total variance was contributed by interindividual variability and is probably representative of the true biologic variability of response to carcinogenic exposure in lymphocytes. The estimated interindividual variability in DNA damage after subtracting intraindividual variability and measurement uncertainty was 24-fold. Inter-individual variance was higher (52-fold) in persons who constitutively lack the Glutathione S-Transferase M1 (GSTM1) gene which is important in the detoxification pathway of PAH. Risk assessment models that do not consider the variability of susceptibility to DNA damage following carcinogen exposure may underestimate risks to the general population, especially for those people who are most vulnerable.     

Human Interindividual Variability in Susceptibility to Airborne Particles

Part of the explanation for the persistent epidemiological findings of associations between mortality and morbidity with relatively modest ambient exposures to airborne particles may be that some people are much more susceptible to particle-induced responses than others. This study assembled a database of quantitative observations of interindividual variability in pharmacokinetic and pharmacodynamic parameters likely to affect particle response. The pharmacodynamic responses studied included data drawn from epidemiologic studies of doses of methacholine, flour dust, and other agents that induce acute changes in lung function. In general, the amount of interindividual variability in several of these pharmacodynamic response parameters was greater than the variability in pharmacokinetic (breathing rate, deposition, and clearance) parameters. Quantitatively the results indicated that human interindividual variability of breathing rates and major pharmacokinetic parameters-total deposition and tracheobronchial clearance-were in the region of Log(GSD) = 0.1 to 0.2 (corresponding to geometric standard deviations of 10(.1)-10(.2) or 1.26-1.58). Deposition to the deep lung (alveolar region) appeared to be somewhat more variable: Log(GSD) of about 0.3 (GSD of about 2). Among pharmacodynamic parameters, changes in FEV1 in response to ozone and metabisulfite (an agent that is said to act primarily on neural receptors in the lung) were in the region of Log(GSD) of 0.2 to 0.4. However, similar responses to methacholine, an agent that acts on smooth muscle, seemed to have still more variability (0.4 to somewhat over 1.0, depending on the type of population studied). Similarly high values were suggested for particulate allergens. Central estimates of this kind of variability, and the close correspondence of the data to lognormal distributions, indicate that 99.9th percentile individuals are likely to respond at doses that are 150 to 450-fold less than would be needed in median individuals. It seems plausible that acute responses with this amount of variability could form part of the mechanistic basis for epidemiological observations of enhanced mortality in relation to ambient exposures to fine particles.     

Modeling Long-Term Exposure of the Whole Population to Chemicals in Food

This paper discusses a statistical exposure model (STEM) that can be used to estimate the percentage of the population exceeding ingestion intake criteria (e.g., ADI or TDI). In addition, STEM may be linked to toxicokinetic models to evaluate the interindividual variability in internal doses that results from variability in consumption habits. The assumptions of STEM are investigated by analyzing dioxin and cadmium intake data for the Dutch population.     

Methods and Rationale for Derivation of a Reference Dose for Methylmercury by the U.S. EPA

In 2001, the U.S. Environmental Protection Agency derived a reference dose (RfD) for methylmercury, which is a daily intake that is likely to be without appreciable risk of deleterious effects during a lifetime. This derivation used a series of benchmark dose (BMD) analyses provided by a National Research Council (NRC) panel convened to assess the health effects of methylmercury. Analyses were performed for a number of endpoints from three large longitudinal cohort studies of the neuropsychological consequences of in utero exposure to methylmercury: the Faroe Islands, Seychelles Islands, and New Zealand studies. Adverse effects were identified in the Faroe Islands and New Zealand studies, but not in the Seychelles Islands. The NRC also performed an integrative analysis of all three studies. The EPA applied a total uncertainty factor (UF) of 10 for intrahuman toxicokinetic and toxicodynamic variability and uncertainty. Dose conversion from cord blood mercury concentrations to maternal methylmercury intake was performed using a one-compartment model. Derivation of potential RfDs from a number of endpoints from the Faroe Islands study converged on 0.1 microg/kg/day, as did the integrative analysis of all three studies. EPA identified several areas for which further information or analyses is needed. Perhaps the most immediately relevant is the ratio of cord:maternal blood mercury concentration, as well as the variability around this ratio. EPA assumed in its dose conversion that the ratio was 1.0; however, available data suggest it is perhaps 1.5-2.0. Verification of a deviation from unity presumably would be translated directly into comparable reduction in the RfD. Other areas that EPA identified as significant areas requiring further attention are cardiovascular consequences of methylmercury exposure and delayed neurotoxicity during aging as a result of previous developmental or adult exposure.     

Variability and Uncertainty in Swedish Exposure Factors for Use in Quantitative Exposure Assessments

Information of exposure factors used in quantitative risk assessments has previously been compiled and reported for U.S. and European populations. However, due to the advancement of science and knowledge, these reports are in continuous need of updating with new data. Equally important is the change over time of many exposure factors related to both physiological characteristics and human behavior. Body weight, skin surface, time use, and dietary habits are some of the most obvious examples covered here. A wealth of data is available from literature not primarily gathered for the purpose of risk assessment. Here we review a number of key exposure factors and compare these factors between northern Europe—here represented by Sweden—and the United States. Many previous compilations of exposure factor data focus on interindividual variability and variability between sexes and age groups, while uncertainty is mainly dealt with in a qualitative way. In this article variability is assessed along with uncertainty. As estimates of central tendency and interindividual variability, mean, standard deviation, skewness, kurtosis, and multiple percentiles were calculated, while uncertainty was characterized using 95% confidence intervals for these parameters. The presented statistics are appropriate for use in deterministic analyses using point estimates for each input parameter as well as in probabilistic assessments.     

Statistical Distributions of Daily Breathing Rates for Narrow Age Groups of Infants and Children

Children may be more susceptible to toxicity from some environmental chemicals than adults. This susceptibility may occur during narrow age periods (windows), which can last from days to years depending on the toxicant. Breathing rates specific to narrow age periods are useful to assess inhalation dose during suspected windows of susceptibility. Because existing breathing rates used in risk assessment are typically for broad age ranges or are based on data not representative of the population, we derived daily breathing rates for narrow age ranges of children designed to be more representative of the current U.S. children's population. These rates were derived using the metabolic conversion method of Layton (1993) and energy intake data adjusted to represent the U.S. population from a relatively recent dietary survey (CSFII 1994–1996, 1998). We calculated conversion factors more specific to children than those previously used. Both nonnormalized (L/day) and normalized (L/kg-day) breathing rates were derived and found comparable to rates derived using energy estimates that are accurate for the individuals sampled but not representative of the population. Estimates of breathing rate variability within a population can be used with stochastic techniques to characterize the range of risk in the population from inhalation exposures. For each age and age-gender group, we present the mean, standard error of the mean, percentiles (50th, 90th, and 95th), geometric mean, standard deviation, 95th percentile, and best-fit parametric models of the breathing rate distributions. The standard errors characterize uncertainty in the parameter estimate, while the percentiles describe the combined interindividual and intra-individual variability of the sampled population. These breathing rates can be used for risk assessment of subchronic and chronic inhalation exposures of narrow age groups of children.     

Combining Food Frequency and Survey Data to Quantify Long-Term Dietary Exposure: A Methyl Mercury Case Study

Twenty-four-hour recall data from the Continuing Survey of Food Intake by Individuals (CSFII) are frequently used to estimate dietary exposure for risk assessment. Food frequency questionnaires are traditional instruments of epidemiological research; however, their application in dietary exposure and risk assessment has been limited. This article presents a probabilistic method of bridging the National Health and Nutrition Examination Survey (NHANES) food frequency and the CSFII data to estimate longitudinal (usual) intake, using a case study of seafood mercury exposures for two population subgroups (females 16 to 49 years and children 1 to 5 years). Two hundred forty-nine CSFII food codes were mapped into 28 NHANES fish/shellfish categories. FDA and state/local seafood mercury data were used. A uniform distribution with minimum and maximum blood-diet ratios of 0.66 to 1.07 was assumed. A probabilistic assessment was conducted to estimate distributions of individual 30-day average daily fish/shellfish intakes, methyl mercury exposure, and blood levels. The upper percentile estimates of fish and shellfish intakes based on the 30-day daily averages were lower than those based on two- and three-day daily averages. These results support previous findings that distributions of "usual" intakes based on a small number of consumption days provide overestimates in the upper percentiles. About 10% of the females (16 to 49 years) and children (1 to 5 years) may be exposed to mercury levels above the EPA's RfD. The predicted 75th and 90th percentile blood mercury levels for the females in the 16-to-49-year group were similar to those reported by NHANES. The predicted 90th percentile blood mercury levels for children in the 1-to-5-year subgroup was similar to NHANES and the 75th percentile estimates were slightly above the NHANES.     

An Exposure Assessment for Methylmercury from Seafood for Consumers in the United States

An exposure model was developed to relate seafood consumption to levels of methylmercury (reported as mercury) in blood and hair in the U.S. population, and two subpopulations defined as children aged 2-5 and women aged 18-45. Seafood consumption was initially modeled using short-term (three-day) U.S.-consumption surveys that recorded the amount of fish eaten per meal. Since longer exposure periods include more eaters with a lower daily mean intake, the consumption distribution was adjusted by broadening the distribution to include more eaters and reducing the distribution mean to keep total population intake constant. The estimate for the total number of eaters was based on long-term purchase diaries. Levels of mercury in canned tuna, swordfish, and shark were based on FDA survey data. The distribution of mercury levels in other species was based on reported mean levels, with the frequency of consumption of each species based on market share. The shape distribution for the given mean was based on the range of variation encountered among shark, tuna, and swordfish. These distributions were integrated with a simulation that estimated average daily intake over a 360-day period, with 10,000 simulated individuals and 1,000 uncertainty iterations. The results of this simulation were then used as an input to a second simulation that modeled levels of mercury in blood and hair. The relationship between dietary intake and blood mercury in a population was modeled from data obtained from a 90-day study with controlled seafood intake. The relationship between blood and hair mercury in a population was modeled from data obtained from several sources. The biomarker simulation employed 2,000 simulated individuals and 1,000 uncertainty iterations. These results were then compared to the recent National Health and Nutrition Examination Survey (NHANES) that tabulated blood and hair mercury levels in a cross-section of the U.S. population. The output of the model and NHANES results were similar for both children and adult women, with predicted mercury biomarker concentrations within a factor of two or less of NHANES biomarker results. However, the model tended to underpredict blood levels for women and overpredict blood and hair levels for children.     

Physiologically-Based Pharmacokinetic Modeling of Benzene in Humans: A Bayesian Approach

Benzene is myelotoxic and leukemogenic in humans exposed at high doses (>1 ppm, more definitely above 10 ppm) for extended periods. However, leukemia risks at lower exposures are uncertain. Benzene occurs widely in the work environment and also indoor air, but mostly below 1 ppm, so assessing the leukemia risks at these low concentrations is important. Here, we describe a human physiologically-based pharmacokinetic (PBPK) model that quantifies tissue doses of benzene and its key metabolites, benzene oxide, phenol, and hydroquinone after inhalation and oral exposures. The model was integrated into a statistical framework that acknowledges sources of variation due to inherent intra- and interindividual variation, measurement error, and other data collection issues. A primary contribution of this work is the estimation of population distributions of key PBPK model parameters. We hypothesized that observed interindividual variability in the dosimetry of benzene and its metabolites resulted primarily from known or estimated variability in key metabolic parameters and that a statistical PBPK model that explicitly included variability in only those metabolic parameters would sufficiently describe the observed variability. We then identified parameter distributions for the PBPK model to characterize observed variability through the use of Markov chain Monte Carlo analysis applied to two data sets. The identified parameter distributions described most of the observed variability, but variability in physiological parameters such as organ weights may also be helpful to faithfully predict the observed human-population variability in benzene dosimetry.     

Influence of Prenatal Mercury Exposure Upon Scholastic and Psychological Test Performance: Benchmark Analysis of a New Zealand Cohort

This paper presents benchmark (BMD) calculations and additional regression analyses of data from a study in which scores from 26 scholastic and psychological tests administered to 237 6- and 7-year-old New Zealand children were correlated with the mercury concentration in their mothers' hair during pregnancy. The original analyses of five test scores found an association between high prenatal mercury exposure and decreased test performance, using category variables for mercury exposure. Our regression analyses, which utilized the actual hair mercury level, did not find significant associations between mercury and children's test scores. However, this finding was highly influenced by a single child whose mother's mercury hair level (86 mgkg) was more than four times that of any other mother. When that child was omitted, results were more indicative of a mercury effect and scores on six tests were significantly associated with the mothers' hair mercury level. BMDs calculated from five tests ranged from 32 to 73 mgkg hair mercury, and corresponding BMDLs (95% lower limits on BMDs) ranged from 17 to 24 mgkg. When the child with the highest mercury level was omitted, BMDs ranged from 13 to 21 mgkg, and corresponding BMDLs ranged from 7.4 to 10 mgkg.     

Reanalysis of Dose-Response Data from the Iraqi Methylmercury Poisoning Episode

Applying a hockey stick parametric dose-response model to data on late or retarded development in Iraqi children exposed in utero to methylmercury, with mercury (Hg) exposure characterized by the peak Hg concentration in mothers'hair during pregnancy, Cox et al. calculated the "best statistical estimate" of the threshold for health effects as 10 ppm Hg in hair with a 95% range of uncertainty of between 0 and 13.6 ppm.⁽¹⁾A new application of the hockey stick model to the Iraqi data shows, however, that the statistical upper limit of the threshold based on the hockey stick model could be as high as 255 ppm. Furthermore, the maximum likelihood estimate of the threshold using a different parametric model is virtually zero. These and other analyses demonstrate that threshold estimates based on parametric models exhibit high statistical variability and model dependency, and are highly sensitive to the precise definition of an abnormal response. Consequently, they are not a reliable basis for setting a reference dose (RfD) for methylmercury. Benchmark analyses and statistical analyses useful for deriving NOAELs are also presented. We believe these latter analyses—particularly the benchmark analyses—generally form a sounder basis for determining RfDs than the type of hockey stick analysis presented by Cox et al. However, the acute nature of the exposures, as well as other limitations in the Iraqi data suggest that other data may be more appropriate for determining acceptable human exposures to methylmercury.     

An Exposure Assessment of Methyl Mercury via Fish Consumption for the Japanese Population

The objective of this article was to propose an exposure assessment model to describe the relationship between fish consumption and body methyl mercury (MeHg) levels in the Japanese population. Individual MeHg intake was estimated by the summation of species-specific fish consumption multiplied by species-specific fish MeHg levels. The distribution of fish consumed by individuals and the MeHg level in each fish species were assigned based on published data from Japanese government institutions. The probability of MeHg intake for a population was accomplished through a Monte Carlo simulation by the random sampling of fish consumption and species-specific MeHg levels. Internal body MeHg levels in blood and hair were estimated using a one-compartment model. Overall, the mean value of MeHg intake for the Japanese population was estimated to be 6.76 μg/day or 0.14 μg/kg body weight per day (bw/day), while the mean value for the hair mercury level was 2.02 μg/g. Compared with the survey data that tabulated hair mercury levels in a cross-section of the Japanese population, the simulation results matched the hair mercury survey data very well for women, but somewhat underestimated for men and all of the population. This exposure assessment model is a useful attempt at further risk assessment with respect to a risk-benefit analysis.     

TCDD Exposure-Response Analysis and Risk Assessment

We examined the relation between cancer mortality and time-dependent cumulative exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) estimated from a concentration- and age-dependent kinetic model of elimination, and we estimated incremental cancer risks at age 75. Data from the National Institute for Occupational Safety and Health study of 3,538 workers with occupational exposure to TCDD were analyzed using standardized mortality ratios and Cox regression procedures. Analyses adjusted for potential confounding by age, year of birth, and race and considered exposure lag periods of 0, 10, or 15 years. Other potential confounders including smoking and other occupational exposures were evaluated indirectly. To explore the influence of extreme values of cumulative TCDD ppt-years, we restricted the analysis to observations with exposure below the 95th percentile or used logarithmic (ln) transformed exposure values. We applied penalized smoothing splines to examine variation in the exposure-response relation across the exposure range. TCDD was not statistically significantly associated with cancer mortality using the full data set, regardless of the lag period. When we restricted the analysis to observations with exposure below the 95th percentile, TCDD was associated positively with cancer mortality, particularly when a 15-year lag was applied (untransformed exposure data: regression coefficient , standard error (s.e.) = 1.4 x 10(-6), p < 0.05; ln-transformed exposure data: , s.e. = 2.9 x 10(-2), p < 0.05). The estimated incremental lifetime risk of mortality at age 75 from all cancers was about 6 to more than 10 times lower than previous estimates derived from this cohort using exposure models that did not consider the age and concentration dependence of TCDD elimination.     

Dermal Versus Total Uptake of Benzene from Mineral Spirits Solvent During Parts Washing

Quantitative approaches to assessing exposure to, and associated risk from, benzene in mineral spirits solvent (MSS), used widely in parts washing and degreasing operations, have focused primarily on the respiratory pathway. The dermal contribution to total benzene uptake from such operations remains uncertain because measuring in vivo experimental dermal uptake of this volatile human carcinogen is difficult. Unprotected dermal uptake involves simultaneous sustained immersion events and transient splash/wipe events, each yielding residues subject to evaporation as well as dermal uptake. A two‐process dermal exposure framework to assess dermal uptake to normal and damaged skin was applied to estimate potential daily dermal benzene dose (D_skin) to workers who used historical or current formulations of recycled MSS in manual parts washers. Measures of evaporation and absorption of MSS dermally applied to human subjects were modeled to estimate in vivo dermal uptake of benzene in MSS. Uncertainty and interindividual variability in D_skin was characterized by Monte Carlo simulation, conditioned on uncertainty and/or variability estimated for each model input. Dermal exposures are estimated to average 33% of total (inhalation + dermal) benzene parts washing dose, with approximately equal predicted portions of dermal dose due to splash/wipe and to continuous contact with MSS. The estimated median (95th percentile) dermal and total daily benzene doses from parts washing are: 0.0069 (0.024) and 0.025 (0.18) mg/day using current, and 0.027 (0.085) and 0.098 (0.69) mg/day using historical, MSS solvents, respectively.     

Development of a Screening Approach to Interpret Human Biomonitoring Data on Volatile Organic Compounds: Reverse Dosimetry on Biomonitoring Data for Trichloroethylene

A screening approach is developed for volatile organic compounds (VOCs) to estimate exposures that correspond to levels measured in fluids and/or tissues in human biomonitoring studies. The approach makes use of a generic physiologically-based pharmacokinetic (PBPK) model coupled with exposure pattern characterization, Monte Carlo analysis, and quantitative structure property relationships (QSPRs). QSPRs are used for VOCs with minimal data to develop chemical-specific parameters needed for the PBPK model. The PBPK model is capable of simulating VOC kinetics following multiple routes of exposure, such as oral exposure via water ingestion and inhalation exposure during shower events. Using published human biomonitoring data of trichloroethylene (TCE), the generic model is evaluated to determine how well it estimates TCE concentrations in blood based on the known drinking water concentrations. In addition, Monte Carlo analysis is conducted to characterize the impact of the following factors: (1) uncertainties in the QSPR-estimated chemical-specific parameters; (2) variability in physiological parameters; and (3) variability in exposure patterns. The results indicate that uncertainty in chemical-specific parameters makes only a minor contribution to the overall variability and uncertainty in the predicted TCE concentrations in blood. The model is used in a reverse dosimetry approach to derive estimates of TCE concentrations in drinking water based on given measurements of TCE in blood, for comparison to the U.S. EPA's Maximum Contaminant Level in drinking water. This example demonstrates how a reverse dosimetry approach can be used to facilitate interpretation of human biomonitoring data in a health risk context by deriving external exposures that are consistent with a biomonitoring data set, thereby permitting comparison with health-based exposure guidelines.     

Evaluation of Methods for Assessing the Oral Bioavailability of Inorganic Mercury in Soil

The risks associated with environmental exposures to inorganic mercury are typically assessed based on toxicity studies conducted with the soluble salt, mercuric chloride (HgCl₂). Evidence indicates, however, that inorganic mercury is present in soil as a variety of compounds and that oral absorption of inorganic mercury decreases with a decrease in the solubility of the mercury compound being studied. Thus, while HgCl₂ is approximately 15–20% bioavailable, the bioavailability of cinnabar (HgS) may be 30- to 60-fold less. The solubility and, hence, bioavailability of inorganic mercury in soil is expected to be substantially less than that of HgCl₂ due to the presence of less soluble compounds and their interactions with soil constituents. Quantification of this difference in bioavailability is important in assessing potential risks associated with exposure to mercury-containing soil. A review of available studies supports the expectation that mercury bioavailability in soils will be reduced. This paper reviews methods for assessing soil metal absorption with consideration of the characteristics of the oral absorption of elemental and inorganic mercury that should be evaluated in designing additional studies. Because of the very slow elimination of mercury in some species, it is recommended that a repeated-dose study be conducted. Such a study would yield an estimate of relative bioavailability based on a comparison of tissue mercury concentrations in animals ingesting soil with those of animals receiving HgCl₂. The dose, age, gender, and species of animal selected are not expected to affect relative bioavailability estimates; however, it is recommended that studies be conducted in two animal species. Rats should be used because they have been used in many studies of mercury absorption and toxicity. A species of large animals such as monkeys, swine, or dogs should also be used to provide confirmation in a species with greater similarities to humans in gastrointestinal physiology and anatomy. Other critical factors in designing these studies, such as selection and characterization of soil samples, are also addressed.     

Development of a Single-Meal Fish Consumption Advisory for Methyl Mercury

Methyl mercury (meHg) contamination of fish is the leading cause of fish consumption advisories in the United States. These advisories have focused upon repeated or chronic exposure, whereas risks during pregnancy may also exist from a single-meal exposure if the fish tissue concentration is high enough. In this study, acute exposure to meHg from a single fish meal was analyzed by using the one-compartment meHg biokinetic model to predict maternal hair concentrations. These concentrations were evaluated against the mercury hair concentration corresponding to the U.S. Environmental Protection Agency's reference dose (RfD), which is intended to protect against neurodevelopmental effects. The one-compartment model was validated against blood concentrations from three datasets in which human subjects ingested meHg in fish, either as a single meal or multiple meals. Model simulations of the single-meal scenario at different fish meHg concentrations found that concentrations of 2.0 ppm or higher can be associated with maternal hair concentrations elevated above the RfD level for days to weeks during gestation. A single-meal fish concentration cutoff of > or = 2.0 ppm is an important consideration, especially because this single high exposure event might be in addition to a baseline meHg body burden from other types of fish consumption. This type of single-meal advisory requires that fish sampling programs provide data for individual rather than composited fish, and take into account seasonal differences that may exist in fish concentrations.     

Bioaccessibility of Fukushima‐Accident‐Derived Cs in Soils and the Contribution of Soil Ingestion to Radiation Doses in Children

Ingestion of contaminated soil is one potential internal exposure pathway in areas contaminated by the Fukushima Daiichi Nuclear Power Plant accident. Doses from this pathway can be overestimated if the availability of radioactive nuclides in soils for the gastrointestinal tract is not considered. The concept of bioaccessibility has been adopted to evaluate this availability based on in vitro tests. This study evaluated the bioaccessibility of radioactive cesium from soils via the physiologically‐based extraction test (PBET) and the extractability of those via an extraction test with 1 mol/L of hydrochloric acid (HCl). The bioaccessibility obtained in the PBET was 5.3% ± 1%, and the extractability in the tests with HCl was 16% ± 3%. The bioaccessibility was strongly correlated with the extractability. This result indicates the possibility that the extractability in HCl can be used as a good predictor of the bioaccessibility with PBET. In addition, we assessed the doses to children from the ingestion of soil via hand‐to‐mouth activity based on our PBET results using a probabilistic approach considering the spatial distribution of radioactive cesium in Date City in Fukushima Prefecture and the interindividual differences in the surveyed amounts of soil ingestion in Japan. The results of this assessment indicate that even if children were to routinely ingest a large amount of soil with relatively high contamination, the radiation doses from this pathway are negligible compared with doses from external exposure owing to deposited radionuclides in Fukushima Prefecture.