Data-Derived Uncertainty Factors: Boric Acid (BA) as a Case Study

There is growing support for the use of data-derived uncertainty factors. In recent years, risk assessments of boric acid have been performed by several well-respected organizations, including IEHR, ECETOC, IPCS, and WHO. For each, the pivotal study was a developmental toxicity study in rats with a no-observed-adverse-effect level (NOAEL) of 55 mg BA/kg/day. These risk assessments employed reduced uncertainty factors in the range of 25 to 60 for boric acid, because available pharmacokinetic data for boric acid reduced uncertainty in evaluating the overall data base with this compound. However, a limitation of previous risk assessments was the absence of specific data on the renal clearance of boric acid in pregnant rats and pregnant women. New data has demonstrated that when renal clearance was normalized to body weight (ml/min/kg), pregnant rats cleared boric acid at a rate roughly three times greater than pregnant women. In addition, the boric acid specific allometric relationship was determined from the log-log plot of clearance vs. body weight. Based on the new renal clearance data, it was estimated that pregnant women and rats would have the same AUC when pregnant women are given 30% of the boric acid dose given to pregnant rats. In addition, the renal clearance of boric acid among pregnant women varied by a factor of about 2. Therefore, boric acid-specific data on renal clearance in pregnant women and rats supports reduced interspecies and intraspecies pharmacokinetic uncertainty factors of approximately 3 and 2, respectively. Further, growing evidence of the essentiality in animals, combined with consistency of effects among species in toxicity studies, suggests a reduced pharmacodynamic uncertainty factor is appropriate for boric acid. Total uncertainty factors in the range of 22 to 44 are scientifically justified for this compound. An acceptable daily intake of 1.25 to 2.5 mg BA/kg/day is estimated by applying an uncertainty factor of 22 to 44 to the NOAEL of 55 mg BA/kg/day. Data-derived uncertainty factors should be used whenever possible, and they should be determined and applied in a consistent manner. Ultimately, estimates based on target tissue dose-adjusted relationships should offer a better approach to risk assessment.     

An Objective Uncertainty Factor Adjustment for Methyl mercury Pharmacokinetic Variability

While default uncertainty factor (UF) adjustments have been proposed for pharmacokinetic variability in the derivation of Reference Doses (RfDs), few attempts have been made to derive chemical-specific UFs for such variability. In recent epidemiologic data on the neuro-developmental effects of MeHg, Hg concentration in either hair or blood is the point-of-departure for RfD derivation. The application of a pharmacokinetic model to derive an intake dose from the measured biomarker concentration allows examination of the inter-individual variability in the relationship between intake dose and biomarker concentration through specification of the variability in model parameters. Three independent studies of this variability, using different models and/or different parameter values, are compared. While differences in central tendency estimates give different predictions of the intake dose corresponding to a given biomarker concentration, normalization of the central tendency estimate resulted in strong agreement among the studies. Starting with Hg concentration in hair or blood, and dividing a central tendency estimate of the corresponding intake dose by a UF of 2 to 3, accounts for 95 to 99% of the variability in the relationship between intake dose and biomarker concentration. This variability, however, encompasses only a portion of the maternal ingestion-to-fetal brain pathway. It is therefore likely that this UF underestimates the overall pharmacokinetic variability in this pathway.     

Separating Pharmacokinetic and Pharmacodynamic Components in Empirical Adjustment Factor Distributions

For a particular chemical, one can treat the chemical-by-chemical variation in relative doses for equal toxicity in experimental animals and humans as a characterization of the likelihoods of extrapolation factors of different magnitudes. An emerging approach to noncancer risk assessment is to use such empirical distributions in place of fixed Uncertainty Factors. This paper discusses dividing the overall variation into two sub-distributions representing pharmacokinetic (PK) and pharmacodynamic (PD) contributions to the variation among chemicals in the animal-to-human toxicologically equivalent dose. If a physiologically based pharmacokinetic model (PBPK model) is used to derive a compound specific adjustment factor (CSAF) for the pharmacokinetic component, the deconvolution of the PK and PD components allows one to remove the PK component (to be replaced with the CSAF), while retaining the uncertainty in pharmacodynamics that PBPK models do not address. One must then add back the uncertainty in the PBPK determination of the CSAF (which may be considerable). A candidate criterion for whether one can use an uncertain PBPK model is whether the generic uncertainty about cross-species pharmacokinetics (reflected in the PK component of the overall empirical distribution) is larger than the chemical-specific uncertainty in the determination of kinetically equivalent doses in experimental animals and humans.     

Replacing the Default Values of 10 With Data-Derived Values: A Comparison of Two Different Data-Derived Uncertainty Factors for Boron

A “safe” or sub-threshold dose is often estimated for oral toxicity of substances in order to protect humans from adverse health effects. This dose is referred to by several terms: reference dose (RfD), tolerable daily intake (TDI), and acceptable daily intake (ADI). Similarly, tolerable concentration (TC), and reference concentration (RfC) are commonly used terms for a “safe” concentration for inhalation. The process of deriving these doses generally involves identifying a no observed, or lowest observed adverse effect level (NOAEL or LOAEL) in animals, or humans, and application of uncertainty factors to account for the extrapolation from laboratory animals to humans and/or from an average human to a sensitive human. Public health agencies have begun to consider using a data derived approach, which uses available toxicokinetic and toxicodynamic data in the determination of uncertainty factors, rather than relying on the standard default values. Recently two different tolerable daily intake risk values were derived by two different World Health Organization (WHO) work groups. The International Programme on Chemical Safety, and the Working Group on Chemical Substances in Drinking Water both used the approach developed by Renwick (1993); however, the two groups interpreted and used the available data differently. The result was a difference of over twofold in the total uncertainty factor used. This review compares and contrasts the two approaches used by these WHO work groups.     

Rationale for the Chemical-Specific Adjustment Factors Used to Derive an Occupational Exposure Limit for Timolol Maleate

Timolol maleate is a non-selective beta-adrenergic blocking agent currently used primarily to reduce intraocular pressure in the treatment of glaucoma. It also produces effects on the heart and bronchial smooth muscle and all of these effects are of potential concern in workers handling this active pharmaceutical ingredient. The disposition of timolol maleate is influenced by a polymorphism in oxidative metabolism by CYP2D6 and two distinct phenotypes have been identified (i.e., poor and extensive metabolizers). These properties of timolol maleate provided an opportunity to use the compound as a case study to demonstrate the derivation of chemical-specific adjustment factors for pharmacokinetics and pharmacodynamics to replace the default uncertainty factor for interindividual variability. Overall, the available data on the pharmacodynamic endpoints showed very little variability and most pharmacokinetic studies failed to discern significant differences in relatively small groups of healthy volunteers or patients. Reports of bradycardia and bronchoconstriction in patients receiving therapeutic doses are relatively rare. In one study, there was a significant reduction in heart rate 24 hours post-dose that was associated with elevated area under the curve (AUC) values. A chemical-specific adjustment factor (CSAF) for kinetics of 9.8 based on these AUC data was combined with a CSAF for dynamics of 1.2 and applied to the extrapolated no-effect level for clinically significant cardiovascular effects (with correction for oral bioavailability) to establish an occupational exposure limit (OEL) for timolol maleate which is expected to be protective of workers that may be poor metabolizers or asthmatics.     

Associations of Proanthocyanidin Intake with Renal Function and Clinical Outcomes in Elderly Women

Background

Progression to chronic renal failure involves accelerated atherosclerosis and vascular calcification. Oxidative stress and endothelial dysfunction play a role in renal failure pathophysiology. In addition to improving vascular health and function, proanthocyanidins have been shown to exert renoprotective effects in animal models. Thus we hypothesize that proanthocyanidins may contribute to the maintenance of healthy renal function.

Objective

Determine the association of habitual proanthocyanidin intake with renal function and the risk of clinical renal outcomes in a population of elderly women.

Design

948 women aged over 75 y, free of prevalent renal disease at baseline, were randomly selected from ambulant Caucasian women. Proanthocyanidin consumption was determined using a validated food frequency questionnaire and the United States Department of Agriculture proanthocyanidin food content database. Fasting serum cystatin C and creatinine were assessed at baseline. Renal failure hospitalisations and deaths were assessed over 5 years of follow-up through the Western Australia Data Linkage System.

Results

Compared to participants with low consumption, participants in the highest tertile of proanthocyanidin intake had a 9% lower cystatin C concentration (P<0.001). High proanthocyanidin consumers were at 50% lower risk of moderate chronic kidney insufficiency, and 65% lower risk of experiencing a 5-year renal disease event (P<0.05). These relationships remained significant following adjustment for renal disease risk factors and diet-related potential confounders.

Conclusion

Increased consumption of proanthocyanidins was associated with better renal function and substantially reduced renal associated events, which has been supported by mechanistic and animal model data. Proanthocyanidin intake should be further examined as a dietary contributor to better renal health.     

Boron tolerable intake

Boron, which is ubiquitous in the environment, causes developmental and reproductive effects in experimental animals. This observation has led to efforts to establish a Tolerable Intake value for boron. Although risk assessors agree on the use of fetal weight decreases observed in rats as an appropriate critical effect, consensus on the adequacy of toxicokinetic data as a basis for replacement of default uncertainty factors remains to be reached. A critical analysis of the existing data on boron toxicokinetics was conducted to clarify the appropriateness of replacing default uncertainty factors (10-fold for interspecies differences and 10-fold for intraspecies differences) with data-derived values. The default uncertainty factor for variability in response from animals to humans of 10-fold (default values of 4-fold for kinetics and 2.5-fold for dynamics) was recommended, since clearance of boron is 3-to 4-fold higher in rats than in humans and data on dynamic differences—in order to modify the default value—are unavailable. A data-derived adjustment of 6-fold (1.8 for kinetics and 3.1 for dynamics) rather than the default uncertainty factor of 10-fold was considered appropriate for intrahuman variability, based on variability in glomerular filtration rate during pregnancy in humans and the lack of available data on dynamic differences. Additional studies to investigate the toxicokinetics of boron in rats would be useful to provide a stronger basis for replacement of default uncertainty factors for interspecies variation.     

The effect of essentiality on risk assessment

Metals are ubiquitous in the human environment, making exposure inevitable and requiring scientifically sound risk assessment methodology to ensure adequate health protection. Within this area, as part of its ongoing efforts to improve and harmonize internationally approaches to risk assessments, the International Program on Chemical Safety (IPCS) has initiated work to improve the risk assessment procedures for essential trace elements (ETEs). Zn, Cu, Se, Cr, and MO are ETEs for humans, with increasing evidence of an essential role for boron (B). For ETEs, there is a range of daily intake within which the organism maintains homeostasis. At intakes below this range, there is an increased risk from deficiency, and at intakes above the range toxicity may develop. Obviously, for ETEs one cannot assume zero exposure is without risk. Adequate health protection will require the cooperative effort of scientists in nutrition and toxicology to develop the limits of the accepted range for ETEs considering such unique properties of metals as bioavailability, speciation, interactions, and biokinetics. Based on previous work by other groups and the recommendations of an IPCS consultation, a scientific monograph will be completed by IPCS. It will examine present risk assessment methodology for ETEs, and develop scientific principles supporting use of a homeostatic model for the development of dietary reference values and tolerable daily intakes. The objective is to develop an internationally accepted methodology for assessing ETEs as part of the IPCS effort to harmonize approaches to risk assessment worldwide. A recent IPCS Task Group on Zn highlighted some of the scientific issues that require resolution to avoid an overlap of the recommended daily intake based on nutritional needs with that based on toxicity and will serve as a case study.     

Baseline alcohol consumption,type of alcoholic beverage and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition-Norfolk study

Excessive alcohol consumption has been associated with increased risk of colorectal cancer (CRC). However, the effect of modest alcohol consumption or of particular types of beverages on CRC risk remains unclear. We examined whether consumption of total alcohol or specific types of alcoholic beverages relate to overall or site-specific CRC risk in a prospective population study of 24,244 participants and 407 incident CRC cases after 11 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. Consumption of specific alcoholic beverages at baseline was collected using a detailed health and lifestyle questionnaire. Total alcohol consumption was not associated with CRC risk before or after adjustment for age, sex, weight, height, and smoking status (HR: 0.80, 95% CI: 0.51–1.26 for alcohol consumption of ≥21 units/week compared with non-drinkers), and further adjustment for education level, exercise, family history of CRC, and dietary factors did not significantly alter the risk estimates (HR: 0.70, 95% CI: 0.44–1.13). No significant associations were observed between consumption of specific alcoholic beverages (beer, sherry, or spirits) and CRC risk when compared with non-drinkers after adjustment for lifestyle and dietary factors. Daily consumption of ≥1 unit of wine appeared inversely related to CRC risk (HR: 0.61, 95% CI: 0.40–0.94). No evidence was found for sex-specific relationships, and further exclusion of cases incident within 3 years of baseline did not change the associations observed. In this population-based UK cohort, we did not find any significant adverse effect of alcohol over the moderate range of intake on colorectal cancer risk.     

Dietary pattern and 20 year mortality in elderly men in Finland,Italy, and The Netherlands: longitudinal cohort study.

OBJECTIVE: To investigate the association of dietary pattern and mortality in international data. DESIGN: Cohort study with 20 years'' follow up of mortality. SETTING: Five cohorts in Finland, the Netherlands, and Italy. SUBJECTS: Population based random sample of 3045 men aged 50-70 years in 1970. MAIN OUTCOME MEASURES: Food intake was estimated using a cross check dietary history. In this dietary survey method, the usual food consumption pattern in the 6-12 months is estimated. A healthy diet indicator was calculated for the dietary pattern, using the World Health Organisation''s guidelines for the prevention of chronic diseases. Vital status was verified after 20 years of follow up, and death rates were calculated. RESULTS: Dietary intake varied greatly in 1970 between the three countries. In Finland and the Netherlands the intake of saturated fatty acids and cholesterol was high and the intake of alcohol was low; in Italy the opposite was observed. In total 1796 men (59%) died during 20 years of follow up. The healthy diet indicator was inversely associated with mortality (P for trend < 0.05). After adjustment for age, smoking, and alcohol consumption, the relative risk in the group with the healthiest diet indicator compared with the group with the least healthy was 0.87 (95% confidence interval 0.77 to 0.98). Estimated relative risks were essentially similar within each country. CONCLUSIONS: Dietary intake of men aged 50-70 is associated with a 20 year, all cause mortality in different cultures. The healthy diet indicator is useful in evaluating the relation of mortality to dietary patterns.     

Associations between omega-3 poly-unsaturated fatty acids from fish consumption and severity of depressive symptoms: an analysis of the 2005-2008 National Health and Nutrition Examination Survey

Fish is the primary source of dietary omega-3 poly-unsaturated fatty acids EPA and DHA, which have been reported to reduce depressive symptoms in clinical trials. We assessed the association between fish consumption and depressive symptoms in a nationally representative sample of 10,480 adults from the 2005-2008 National Health and Nutrition Examination Survey. Depressive symptoms were classified by severity using the Patient Health Questionnaire. Fish meal consumption reported in 30-day food frequency questionnaires, and EPA+DHA intake computed from 24-h dietary recalls were evaluated in relation to depressive symptoms using multivariable ordinal logistic regression. Consumption of breaded fish showed an increased risk of greater depressive symptom severity, while all fish, non-breaded fish, and shell fish were not associated. Any EPA+DHA intake was significantly associated with fewer depressive symptoms. Exposure-response analyses revealed no clear patterns for any intake measures. Inconsistent patterns of associations in our study may be partially explained by exposure misclassification.     

Dietary calcium,physical activity,and risk of hip fracture: a prospective study.

OBJECTIVE--To determine whether low dietary calcium intake and physical inactivity are risk factors for hip fracture among subjects aged 65 and over. DESIGN--Fifteen year follow up study of a large cohort of randomly selected elderly people living in the community, who had taken part in the 1973-4 survey of the Department of Health and Social Security, and for whom dietary and other data were recorded at initial interview and medical assessment. SETTING--Eight areas in Britain (England (five), Wales (one), and Scotland (two]. SUBJECTS--1688 Subjects living in the community, of whom 1419 subjects (720 men and 699 women) agreed to participate. 1356 Subjects completed a seven day dietary record and 983 (542 men and 441 women) agreed to be assessed by a geriatrician. RESULTS--Incidence of hip fracture increased with age and was higher in women than men. Comparison with matched controls showed no evidence that the risk of hip fracture was related to calcium intake: the odds ratio for the lowest third of dietary calcium compared with the highest was 0.7 (95% confidence interval 0.1 to 3.9) after adjustment for smoking and body mass index. The adjusted odds ratio for the lowest third of outdoor activity compared with the highest was 4.3 (0.7 to 26.8), and that for grip strength was 3.9 (0.7 to 23.0). CONCLUSIONS--Reduced intake of dietary calcium does not seem to be a risk factor for hip fracture. Further evidence is provided that physical activity in the elderly protects against hip fracture.     

Dietary fibre and colon cancer: epidemiologic and experimental evidence.

Epidemiologic studies have identified two dietary factors, a relatively high intake of fat and a relatively low intake of fibre, that are associated with colon cancer in humans. However, a recent study has shown a low risk of large bowel cancer in a rural Finnish population with a high dietary intake of fat, but also a high intake of fibre. Observations in humans and studies in animals have indicated that dietary fibre may protect against colon carcinogenesis by binding bile acids in the intestinal tract, by a direct effect on the colonic mucosa and by an indirect effect on the metabolism of carcinogens. The strength of protection varies with the type of fibre.     

Assessing Risks of Plant-Based Pharmaceuticals: I. Human Dietary Exposure

Protein-based drugs are the fastest growing class of drugs for the treatment of disease in humans and other animals. However, the current method of producing proteins for pharmaceutical application is predicted to fall short because of population growth and demographic trends. This study characterized human dietary risks using quantitative risk assessment techniques for three pharmaceutical proteins produced in field-grown maize. The three proteins were aprotinin, gastric lipase, and Escherichia coli heat-labile enterotoxin B subunit (LT-B). The human dietary risks from the three proteins inadvertently occurring in food were evaluated using three different exposure scenarios so that potential risks could be compared. The three exposure scenarios ranged in conservatism to evaluate the range of risk between the proteins and scenarios. Risk quotients (RQs) were calculated for all three scenarios to integrate exposure and effect (toxicity). The risk assessments revealed that the most conservative scenario produced higher RQs than the other two scenarios. The dietary risks from scenario 1 for aprotinin were three orders of magnitude greater than for scenario 2, and four orders of magnitude greater than for scenario 3. This risk assessment revealed that dietary risks will vary dramatically and depend on factors such as the specific pharmaceutical protein, protein expression, and exposure scenarios. The assessment also reinforced the need for case-by-case assessments.     

Tolerable amounts of amino acids for human supplementation: summary and lessons from published peer-reviewed studies

Amino acid supplementation may be indicated to correct for insufficient amino acid intake in healthy individuals, and in specific physiological or pathophysiological situations. However, there is a concern to not supplement beyond the tolerable upper intake level (UL) by determining parameters of no-observed-adverse-effect level (NOAEL) or lowest-observed-adverse-effect level (LOAEL) for each amino acid. Since the NOAEL and LOAEL values are at least one order of magnitude different when comparing the values obtained in rats and humans, the aim of this review is to evaluate to what extent the amino acid UL measured in the rat model, when referenced to the dietary usual consumption (UC) and dietary requirement (RQ) for indispensable amino acids, may be used as an approximation of the UL in humans. This review then compares the ratios of the NOAEL or LOAEL over UC and RQ in the rat model with the same ratios calculated in humans for the nine amino acids (arginine, serine, glycine, histidine, leucine, lysine, methionine, phenylalanine, and tryptophan) for which this comparison can be done. From the calculations made, it appears that for these 9 amino acids, the calculated ratios for rats and humans, although rather different for several amino acids, remains for all of them in the same order of magnitude. For tryptophan, tyrosine, and valine, the ratios calculated in rats are markedly different according to the sex of animals, raising the view that it may be also the case in humans.

     

Longitudinal associations between key dietary behaviors and weight gain over time: transitions through the adolescent years

Previous studies have yielded inconsistent results when documenting the association between key dietary factors and adolescent weight change over time. The purpose of this study was to examine the extent to which changes in adolescent sugar-sweetened beverage (SSB), diet soda, breakfast, and fast-food consumption were associated with changes in BMI and percent body fat (PBF). This study analyzed data from a sample of 693 Minnesota adolescents followed over 2 years. Random coefficient models were used to examine the relationship between dietary intake and BMI and PBF and to separate cross-sectional and longitudinal associations. Adjusting for total physical activity, total energy intake, puberty, race, socioeconomic status, and age, cross-sectional findings indicated that for both males and females, breakfast consumption was significantly and inversely associated with BMI and PBF, and diet soda intake was significantly and positively associated with BMI and PBF among females. In longitudinal analyses, however, there were fewer significant associations. Among males there was evidence of a significant longitudinal association between SSB consumption and PBF; after adjustment for energy intake, an increase of one serving of SSB per day was associated with an increase of 0.7 units of PBF among males. This study adds to previous research through its methodological strengths, including adjustment for physical activity and energy intake assessed using state-of-the-art methods (i.e., accelerometers and 24-h dietary recalls), as well as its evaluation of both BMI and PBF. Additional research is needed to better understand the complex constellation of factors that contribute to adolescent weight gain over time.     

Cadmium Exposure in the South Korean Population: Implications of Input Assumptions for Deterministic Dietary Assessment

Dietary exposure to Cadmium (Cd) is of increasing interest globally because of the adverse health effects of Cd arising from multiple sources. The assumptions used when undertaking deterministic assessment of Cd in global or regional diets have implications when applied to specific national cases representing local variation in food composition and consumption patterns different from global or regional norms. We have conducted deterministic dietary Cd exposure assessments for the South Korean population using a variety of schemes for point estimation. Consumption data from the Korean Nutrition Survey (2001 to 2003) and monitoring data from the Korea Food and Drug Administration were used as the basis for the exposure estimates. The average daily per capita Cd exposure was 14 μ g for the South Korean population, representing about 27% of tolerable daily intake (TDI) and is similar to that reported in other countries. The hazard index (HI, the ratio of total Cd exposure to the TDI) typically ranged from 0.3 to 0.9 depending on assumptions used in deterministic estimates of dietary exposure. Even though the current exposure of the South Korean population at large is found to be safe on the basis of these estimates, consideration of high-end patterns of Cd level and consumption suggests the need for continued vigilance in dietary Cd monitoring.     

Toxic Metals and Trace Elements in Artisanal Honeys from the Canary Islands

Honey is a natural product made by honey bees from the nectar of flowers or secretions produced by other living plant parts. The metal content of the honeys is related to the levels of metals in the environment. Due to the importance of honey in the human diet and the increase of environmental pollution, it is necessary to determine the content of metals in honey to evaluate the toxicological risk derived from its consumption. The objective of this study was to determine the content of 20 metals (Al, B, Ba, Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, Pb, Sr, V, and Zn) in different samples of artisanal honey from the Canary Islands (Spain) in order to evaluate the dietary intake derived from the consumption of these honeys. A total of 161 samples of different types of Canary honey were analyzed by ICP-OES (inductively coupled plasma–optical emission spectrometry). K (825 mg/kg) was the macroelement found in highest concentration, while B (4.25 mg/kg) was the trace element with the highest mean concentration. Al (3.33 mg/kg) was the most abundant toxic metal, followed by Pb (0.040 mg/kg) and Cd (0.002 mg/kg). A mean consumption of 25 g/day of honey mainly contributes to the recommended daily intake of Cu (1.34% adults) and K (0.67% adults). As regards the toxic metals, the contribution percentage to the TDI (tolerable daily intake) of Pb at 2.92% for adults is noteworthy. However, the consumption of honey does not imply a high intake of metals and, therefore, does pose a risk to the health of adult men and women.

     

Determining human dietary requirements for boron

A dietary requirement is defined as the lowest continuing intake of a nutrient that for a specified indicator of adequacy, will maintain a defined level of nutriture in an individual. An essential dietary component is one that the body cannot synthesize in sufficient quantities to maintain health. Recommended dietary allowances (RDAs) are based on estimates of the dietary requirements, and are designed to prevent deficiency diseases and promote health through an adequate diet. In 1996, the Food and Nutrition Board (FNB) began a revision process of the RDAs using as criteria specific indicators of adequacy and functional end points for reducing the risk of chronic disease. Boron (B) is a dietary component, and evidence from animal studies indicates that it is a dietary essential; it cannot be synthesized in tissues, and organisms exposed to very low levels of B show developmental defects. In humans, there is evidence of homeostatic regulation of B and an interrelationship with bone metabolism. To understand better the relationship between dietary B and B homeostasis, we measured the dietary B intake and urinary B losses in seven male participants of a controlled metabolic study of Zn homeostasis. Average dietary B intake for the repeated menu days, days 1, 2, and 3, was 4.56, 1.87, and 4.75 mg/d, respectively. Urinary B excretion during the 42-d collection period averaged 3.20 ± 0.41 mg/d. When dietary B was low, urinary B loss (2.92 mg/d) was significantly lower than when B intake was higher (3.15 and 3.54 mg/d). Our study showed that urinary B excretion changes rapidly with changes in B intake, indicating that the kidney is the site of homeostatic regulation. To enable establishment of a dietary requirement for B in the future, further research of homeostatic regulation and functional markers of B metabolism need to be performed, followed by epidemiological studies to identify health conditions associated with inadequate dietary B.     

Intake of Inorganic Arsenic in the North American Diet

Dietary intake of inorganic arsenic, previously assumed to be an insignificant source of arsenic exposure in humans, was estimated for Canadian and United States populations. Input data included arsenic contents of various food groups, a limited historical database from the Ontario Ministry of the Environment measuring the percent inorganic arsenic in food groups, and food consumption data. Estimated daily dietary intake of inorganic arsenic ranges from 8.3 to 14?µg/day in the United States and from 4.8 to 12.7?µg/day in Canada for various age groups. These data suggest that between 21% to 40% of total dietary arsenic occurs in inorganic forms. Uncertainties regarding total arsenic in dairy products in the data set applied here may account for observed differences between United States and Canadian estimates. While estimates provided here are preliminary because of limitations in data on the proportion of inorganic arsenic in foods, this analysis suggests that dietary intake of inorganic arsenic is higher than is currently assumed. Additional research is needed to more fully characterize inorganic arsenic concentrations in foods. Future study is also needed on the variability of total and inorganic arsenic in foods and the bioavailability of dietary inorganic arsenic.