Net effects explains the benefits to children from maternal fish consumption despite methylmercury in fish.

In 2001 the U.S. Food and Drug Administration (FDA) issued precautionary advice to pregnant women to limit fish consumption over concern that the methylmercury content might harm their children's neurodevelopment. This concern was based largely on results from an epidemiological study of mothers primarily exposed to methylmercury from consuming pilot whale. Subsequently, FDA and the World Health Organization/Food and Agriculture Organization (WHO/FAO) undertook independent assessments of fish consumption that considered net effects from both fish nutrients, primarily omega-3 fatty acids, as beneficial and methylmercury as harmful. Both assessments estimated that when mothers regularly consume fish during pregnancy, their children are likely to have improved neurodevelopment compared to children of non-fish eaters despite their exposure to methylmercury. These estimated improvements included gains of two to over five full scale IQ points from levels of maternal consumption that are achievable in most of the world. Consistent with those estimates, human research on fish consumption and child neurodevelopment from more than 200,000 mother-child pairs now collectively reports 51 beneficial associations with neurodevelopmental outcomes and three adverse associations, the latter with no discernable pattern. These associations include full scale IQ gains similar to, or somewhat higher than, those estimated by FDA and FAO/WHO. Also consistent with the FDA and FAO/WHO estimates, research has reported beneficial associations with fish consumption when pregnant women are exposed to methylmercury from fish in excess of the U.S. Environmental Protection Agency's (EPA) Reference Dose (RfD). Our analysis evaluates how the net effects approach as utilized by FDA and FAO/WHO provides a holistic explanation for these results with implications for public health policy. This concordance of net effects modeling and empirical scientific evidence supports a clarification of current public health recommendations to focus on greater fish consumption by pregnant women for their children's neurodevelopment.

Estimates of the 2015 global and regional disease burden from four foodborne metals - arsenic, cadmium, lead and methylmercury.

The impact of foodborne metals on the burden of disease has been largely overlooked, in comparison to the attention on acute diseases associated with infectious foodborne agents. Four articles in this special section describe in detail the burden of disease from foodborne lead, methylmercury, arsenic, and cadmium. Ingested lead and methylmercury are causally associated with lifelong intellectual disability. Long term ingestion of arsenic is causally associated with an increased risk of cancer. Long term ingestion of cadmium is causally associated with an increased risk of late stage chronic kidney disease. This article presents an overview of the burden of disease from these four foodborne metals and discusses them in the context of the World Health Organization's initiative to estimate the global burden of foodborne disease. The results indicate that in 2015, ingestion of arsenic, methylmercury, lead, and cadmium resulted in more than 1 million illnesses, over 56,000 deaths, and more than 9 million disability-adjusted life years (DALYs) worldwide. The greatest impact on DALYs was in the Western Pacific B subregion. All of the metals were found to have high DALYs per case in comparison with other foodborne disease agents, including infectious and parasitic agents. In addition, lead, arsenic, and methylmercury were found to have high DALYs per 100,000 population in comparison to other foodborne disease agents.

Global burden of intellectual disability resulting from dietary exposure to lead, 2015.

Lead is a ubiquitous dietary contaminant that occurs in food because of natural and anthropogenic sources and pathways of exposure. Lead adversely affects a number of tissues and organ systems and the severity of effect on each is dependent on the level and duration of exposure. The most sensitive and notable effects are those that occur on the nervous system. This is particularly the case in the exposure to the fetus, infant and child. Infants and children generally have higher lead exposures on a body weight basis. While lead exposure can come from many sources, a major source of exposure for at least some individuals comes from food. Estimates for the impact of dietary lead on IQ were developed from published total diet studies. While most of these were designed to characterize intake of chemical contaminants on a national basis, some sampled market baskets from a single city. To develop global estimates, default ranges were created for countries with no data which encompassed the values encountered elsewhere. Blood lead levels and IQ decrements were estimated using functions previously developed by the WHO Joint Expert Committee for Food Additives. Since both the exposure and dose response components were variable and uncertain, a two dimensional Monte-Carlo simulation was used to develop the estimates for the impact of dietary lead on IQ. In addition to estimating blood lead and IQ decrements attributable to dietary lead from those countries with published market basket data, simulations were also run for WHO regions that sampled in the variability dimension based on the population size of the individual countries in each region. Dietary exposure to lead occurs throughout the world. The global average IQ decrement attributable to dietary lead was 1.1. The total number of Disability-Adjusted Life Years (DALYs) arising from those IQ decrements were estimated to be 5.2 million DALYs, with an uncertainty range of 0-31 million DALYs. Significant uncertainties regarding exposure and dose-response relationships, however, warrant continued investigation.

Global burden of late-stage chronic kidney disease resulting from dietary exposure to cadmium, 2015.

Chronic exposures to cadmium (Cd) are associated with reduced glomerular filtration rate (GFR), increasing the risk of chronic kidney disease (CKD). In support of the World Health Organization (WHO)'s initiative to estimate the global burden of foodborne diseases, a risk assessment was performed to estimate the Disability-Adjusted Life Years (DALYs) due to late-stage CKD associated with dietary exposures to cadmium. Using the distribution of population GFRs, the prevalence of CKD was calculated as the proportion of humans whose GFR fall in the ranges corresponding to Stage 4 or Stage 5 CKD. The increase in the CKD prevalence due to cadmium exposure was simulated based on a previously reported pharmacokinetic model describing the relationship between dietary cadmium intake and urinary cadmium (UCd), as well as a previously published dose-response relationship between UCd and GFR. Cadmium-related incidence rate, calculated as the change in the prevalence during a one-year period, were used to compute the mortality and DALY in all WHO regions. It is estimated that dietary cadmium would result in a median of 12,224 stage 4 and stage 5 new CKD cases per year worldwide, resulting in 2064 global deaths and 70,513 DALYs. These data translate into a median global burden of 1.0 DALY per 100,000 population, which account for 0.2% of the global DALYs of CKD. While these results suggest that the overall impact of dietary cadmium exposure on global CKD is low, they do indicate that reasonable efforts to reduce dietary exposure will result a positive public health impact. This would be particularly the case in areas with elevated levels of dietary cadmium.

World Health Organization estimates of the global and regional disease burden of four foodborne chemical toxins, 2010: a data synthesis.

Background Chemical exposures have been associated with a variety of health effects; however, little is known about the global disease burden from foodborne chemicals. Food can be a major pathway for the general population's exposure to chemicals, and for some chemicals, it accounts for almost 100% of exposure.  Methods and Findings Groups of foodborne chemicals, both natural and anthropogenic, were evaluated for their ability to contribute to the burden of disease.  The results of the analyses on four chemicals are presented here - cyanide in cassava, peanut allergen, aflatoxin, and dioxin.  Systematic reviews of the literature were conducted to develop age- and sex-specific disease incidence and mortality estimates due to these chemicals.  From these estimates, the numbers of cases, deaths and disability adjusted life years (DALYs) were calculated.  For these four chemicals combined, the total number of illnesses, deaths, and DALYs in 2010 is estimated to be 339,000 (95% uncertainty interval [UI]: 186,000-1,239,000); 20,000 (95% UI: 8,000-52,000); and 1,012,000 (95% UI: 562,000-2,822,000), respectively.  Both cyanide in cassava and aflatoxin are associated with diseases with high case-fatality ratios.  Virtually all human exposure to these four chemicals is through the food supply.  Conclusion Chemicals in the food supply, as evidenced by the results for only four chemicals, can have a significant impact on the global burden of disease. The case-fatality rates for these four chemicals range from low (e.g., peanut allergen) to extremely high (aflatoxin and liver cancer).  The effects associated with these four chemicals are neurologic (cyanide in cassava), cancer (aflatoxin), allergic response (peanut allergen), endocrine (dioxin), and reproductive (dioxin).

A proposed framework for assessing risk from less-than-lifetime exposures to carcinogens.

Quantitative methods for estimation of cancer risk have been developed for daily, lifetime human exposures. There are a variety of studies or methodologies available to address less-than-lifetime exposures. However, a common framework for evaluating risk from less-than-lifetime exposures (including short-term and/or intermittent exposures) does not exist, which could result in inconsistencies in risk assessment practice. To address this risk assessment need, a committee of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute conducted a multisector workshop in late 2009 to discuss available literature, different methodologies, and a proposed framework. The proposed framework provides a decision tree and guidance for cancer risk assessments for less-than-lifetime exposures based on current knowledge of mode of action and dose-response. Available data from rodent studies and epidemiological studies involving less-than-lifetime exposures are considered, in addition to statistical approaches described in the literature for evaluating the impact of changing the dose rate and exposure duration for exposure to carcinogens. The decision tree also provides for scenarios in which an assumption of potential carcinogenicity is appropriate (e.g., based on structural alerts or genotoxicity data), but bioassay or other data are lacking from which a chemical-specific cancer potency can be determined. This paper presents an overview of the rationale for the workshop, reviews historical background, describes the proposed framework for assessing less-than-lifetime exposures to potential human carcinogens, and suggests next steps.

Application of the Margin of Exposure (MOE) approach to substances in food that are genotoxic and carcinogenic.

This paper presents the work of an expert group established by the International Life Sciences Institute - European branch (ILSI Europe) to follow up the recommendations of an international conference on "Risk Assessment of Compounds that are both Genotoxic and Carcinogenic: New Approaches". Twelve genotoxic and carcinogenic chemicals that can be present in food were selected for calculation of a Margin of Exposure (MOE) between a point of departure on the dose-response for oral carcinogenicity in animal studies and estimates of human dietary exposure. The MOE can be used to support prioritisation of risk management action and, if the MOE is very large, on communication of a low level of human health concern. Depending on the approaches taken in determining the point of departure and the estimation of exposure, it is possible to derive very different values for the MOE. It is therefore essential that the selection of the cancer endpoint and mathematical treatment of the data are clearly described and justified if the results of the MOE approach are to be trusted and of value to risk managers. An outline framework for calculating an MOE is proposed in order to help to ensure transparency in the results.

The limits of regulatory toxicology.

The Acceptable Daily Intake (ADI) has been used by regulatory and public health organizations (e.g., the U.S. Food and Drug and Administration, and the World Health Organization) for chemicals for more than 50 years. The ADI concept was also initially employed at the U.S. Environmental Protection Agency at its inception in 1971, although with the adoption of newer terminology, it later became known as the Reference Dose (RfD). It is clear from the literature that both were first devised as instruments of regulatory policy. In the intervening years, it has become common to use language that implies that these standards are statements of scientific fact. Similarly, some of the discretionary or default values that are used to derive regulatory standards are represented as scientific assumptions when in fact they also represent regulatory policy. This confusion impedes both the best use of the available science and informed public participation in policy making. In addition, the misconception of the ADI or the RfD as statements of scientific fact may impede the consideration of alternative means to reduce exposure to chemicals that may be harmful, including regulatory measures that do not involve prescribing a regulatory concentration limit.

Lead in women's and children's vitamins.

A survey was conducted to determine the extent of lead (Pb) contamination in vitamins labeled for use by women and children. The Pb content of 324 multivitamin-mineral products was determined using microwave assisted nitric acid digestion and inductively coupled plasma mass spectrometry. Cryogenic grinding was used to composite soft samples such as oil filled capsules and candy-like products such as gummies and jelly beans. Estimates of Pb exposures from consumption of these products were derived for four population groups: young children (0-6 yrs), older children (7+ yrs), pregnant or lactating women, and adult women. The estimated median and maximum Pb exposures were 0.123 and 2.88 microg/day for young children, 0.356 and 1.78 microg/day for older children, 0.845 and 8.97 microg/day for pregnant and lactating women, and 0.842 and 4.92 microg/day for adult women. The overall median value for Pb exposure was 0.576 microg/day. Five samples would have provided exposures that exceeded 4 microg/day. Estimates of exposures were assessed with respect to safe/tolerable exposure levels that have been developed for the specific age and sex groups. These safe/tolerable levels are referred to as the provisional total tolerable intake levels (PTTI) and are 6, 15, 25, and 75 microg Pb/day for young children, older children, pregnant or lactating women, and adult women, respectively. Estimates of Pb exposures were below the PTTI levels for the four population groups. Median and maximum values were used instead of the mean and standard deviation because of the skewed distribution of results toward lower mass fraction and exposure.

Biological stress response terminology: Integrating the concepts of adaptive response and preconditioning stress within a hormetic dose-response framework.

Many biological subdisciplines that regularly assess dose-response relationships have identified an evolutionarily conserved process in which a low dose of a stressful stimulus activates an adaptive response that increases the resistance of the cell or organism to a moderate to severe level of stress. Due to a lack of frequent interaction among scientists in these many areas, there has emerged a broad range of terms that describe such dose-response relationships. This situation has become problematic because the different terms describe a family of similar biological responses (e.g., adaptive response, preconditioning, hormesis), adversely affecting interdisciplinary communication, and possibly even obscuring generalizable features and central biological concepts. With support from scientists in a broad range of disciplines, this article offers a set of recommendations we believe can achieve greater conceptual harmony in dose-response terminology, as well as better understanding and communication across the broad spectrum of biological disciplines.

Tetrachlorodibenzo-p-dioxin in baby food made from chicken produced before and after the termination of ball clay use in chicken feed in the United States.

Polychlorodibenzo-p-dioxin/furans were determined in chicken-containing baby foods collected from an annually conducted total diet survey by the US FDA during the last half of fiscal year (FY) 1997 through the first half of FY 1998. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) was found in 8 of 11 baby food samples. The levels were between 0.025 and 0.28 ng kg(-1) wet wt (0.25-5 ng kg(-1) lipid). The mean TCDD value for chicken-containing baby food with "nondetects" equal to 0 was 1.2 ng kg(-1) lipid, eight times higher than the average level found during a previous survey of chicken lipid TCDD levels in 1996. All other 2,3,7,8-chlorine-substituted dibenzo-p-dioxin congeners were also found with a profile consistent with the use of ball clay in chicken feed. TCDD was not detected in any FY 2000 baby foods made with chicken, with an average limit of detection (LOD) of 0.025 ng kg(-1) wet wt. Whole eggs collected in 1997 from producers that never used ball clay in feed revealed TCDD measurements that were nearly all nondetects and none above the median LOD of 0.015 ng kg(-1) wet wt. The percentage of chickens fed ball clay in their feed was estimated to be between 2.6% and 3.5% of all chickens produced in the United States in 1997.

Hair mercury levels in U.S. children and women of childbearing age: reference range data from NHANES 1999-2000.

Exposure to methyl mercury, a risk factor for neurodevelopmental toxicity, was assessed in U.S. children 1-5 years of age (n = 838) and women 16-49 years of age (n = 1,726) using hair mercury analysis during the 1999-2000 National Health and Nutrition Examination Survey (NHANES). The data are nationally representative and are based on analysis of cross-sectional data for the noninstitutionalized, U.S. household population. The survey consisted of interviews conducted in participants' homes and standardized health examinations conducted in mobile examination centers. Distributions of total hair mercury levels expressed as micrograms per gram hair Hg and the association of hair Hg levels with sociodemographic characteristics and fish consumption are reported. Geometric mean (standard error of the geometric mean) hair mercury was 0.12 microg/g (0.01 microg/g) in children, and 0.20 microg/g (0.02 microg/g) in women. Among frequent fish consumers, geometric mean hair mercury levels were 3-fold higher for women (0.38 vs. 0.11 micro g/g) and 2-fold higher for children (0.16 vs. 0.08 microg/g) compared with nonconsumers. The NHANES 1999-2000 data provide population-based data on hair mercury concentrations for women and children in the United States. Hair mercury levels were associated with age and fish consumption frequency.

Blood mercury levels in US children and women of childbearing age, 1999-2000.

CONTEXT: Humans are exposed to methylmercury, a well-established neurotoxin, through fish consumption. The fetus is most sensitive to the adverse effects of exposure. The extent of exposure to methylmercury in US women of reproductive age is not known. OBJECTIVE: To describe the distribution of blood mercury levels in US children and women of childbearing age and the association with sociodemographic characteristics and fish consumption. DESIGN AND SETTING: The 1999-2000 data from the National Health and Nutrition Examination Survey, a cross-sectional survey of the noninstitutionalized US population. PARTICIPANTS: In 1999-2000, 1250 children aged 1 to 5 years and 2314 women aged 16 to 49 years were selected to participate in the survey. Household interviews, physical examinations, and blood mercury levels assessments were performed on 705 children (56% response rate) and 1709 women (74% response rate). MAIN OUTCOME MEASURE: Blood concentration of total mercury. RESULTS: Blood mercury levels were approximately 3-fold higher in women compared with children. The geometric mean concentration of total blood mercury was 0.34 micro g/L (95% confidence interval [CI], 0.30-0.39 microg/L) in children and 1.02 microg/L (95% CI, 0.85-1.20 microg/L) in women. Geometric mean mercury levels were almost 4-fold higher among women who ate 3 or more servings of fish in the past 30 days compared with women who ate no fish in that period (1.94 microg/L vs 0.51 microg/L; P<.001). CONCLUSIONS: Measures of mercury exposure in women of childbearing age and young children generally fall below levels of concern. However, approximately 8% of women had concentrations higher than the US Environmental Protection Agency's recommended reference dose (5.8 microg/L), below which exposures are considered to be without adverse effects. Women who are pregnant or who intend to become pregnant should follow federal and state advisories on consumption of fish.

Analysis of dietary supplements for arsenic, cadmium, mercury, and lead using inductively coupled plasma mass spectrometry.

The arsenic, cadmium, mercury, and lead contents of 95 dietary supplement products were determined using microwave digestion and high-resolution inductively coupled plasma mass spectrometry. Precision and accuracy were demonstrated by element recovery from 17 dietary supplements and replicates of 8 reference materials. The concentration ranges were as follows: arsenic, <5-3770 microg/kg; cadmium, <10-368 microg/kg; mercury, <80-16800 microg/kg; and lead, <20-48600 microg/kg. An assessment of estimated exposures/intakes of the four elements is presented.