Systematic review and quality ranking of studies of two phthalate metabolites and anogenital distance, bone health, inflammation, and oxidative stress.

Phthalates are ubiquitous chemical compounds, and two-di-ethyl phthalate (DEP) and di-isobutyl phthalate (DiBP)-are not currently regulated by the U.S. Congress or the European Union. While many reviews of phthalates have been published, none have examined bone health, inflammation, or oxidative stress; anogenital distance was most recently reviewed in 2014. The objective of this paper is to determine if an association exists between mono-ethyl phthalate (MEP) or mono-isobutyl phthalate (MiBP), metabolites of DEP and DiBP, respectively, and the four outcomes indicated above. We conducted a literature search of PubMed through December 2017 and included 29 observational epidemiologic studies published in English that assessed MEP and/or MiBP in relation to one of the above four health outcomes in humans. Two authors rated each paper using a modified Downs and Black (DB) assessment tool; a third author settled score disagreements. A single author extracted information related to the study population, exposure and outcome assessment, covariates, and significant results from each article. Ten studies were identified on anogenital distance, four on bone health, five on inflammation, and thirteen on oxidative stress. Score percentages (total points given out of total possible points) were calculated for each study. The current research suggests a positive association between MiBP and two measures of oxidative stress, 8-hydroxydeoxyguanosine (8-OHdG) and 8-isoprostane. MEP is potentially associated with 8-OHdG as well, although the evidence is limited by fewer high-quality studies. There does not appear to be an association between anogenital distance and MEP or MiBP, and it is unclear if relationships exist between these phthalate metabolites and bone health and inflammation. Given the role that oxidative stress plays in a number of diseases and the ubiquity of MEP and MiBP, it is important that individuals be aware of potential sources of exposure to these chemicals.

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 intellectual disability resulting from prenatal exposure to methylmercury, 2015.

We describe analyses to estimate the global burden of disease associated with methylmercury (MeHg). An intelligence quotient < 70, indicating intellectual disability (ID), was selected as the critical disease, maternal hair Hg concentration during pregnancy selected as the critical exposure biomarker, and a dose-effect relationship of an 0.18 point IQ reduction per µg/g increase in maternal hair Hg was assumed, based on a meta-analysis. A systematic review was conducted to obtain country-specific data on the distribution of maternal hair Hg concentrations. The country-specific incidence of MeHg-associated ID was calculated, and a random effects model was used to impute the incidence for countries for which no exposure data could be found. The global burden of MeHg-associated ID was quantified in terms of Disability-Adjusted Life Years (DALYs) using the World Health Organization (WHO) Global Health Estimates methodology, and presented by 14 subregions. In 2015, the global total for MeHg-associated cases of ID was 226,655; 210,074 of these cases (93%) were mild cases of ID. The highest rate of ID (6 cases per 100,000 population) was found in the Americas D subregion. The global DALY estimate was 1,963,869. The Western Pacific B subregion contributed the most to this total (696,417), although the Americas D subregion had the greatest rate (54 DALYs per 100,000 population). The burden of disease associated with MeHg is therefore highly subregion-dependent even in areas that are geographically related. The priority given to reducing this burden can therefore be expected to vary considerably by subregion depending on other health needs.

Global burden of cancer and coronary heart disease resulting from dietary exposure to arsenic, 2015.

Arsenic is a ubiquitous, naturally occurring metalloid that poses a significant risk for human cancer and non-cancer diseases. It is now evident that arsenic contamination in food, especially rice and grains, presents a significant exposure to hundreds of millions of individuals worldwide. However, the disease risk from chronic exposure to the low amounts of arsenic found in food remains to be established. Thus, this research estimates the global burdens of disease expressed as Disability-Adjusted Life Years (DALYs) for lung, skin and bladder cancers, as well as coronary heart disease (CHD) attributable to inorganic arsenic in food. To determine foodborne inorganic arsenic exposures worldwide, we used the World Health Organization (WHO) estimates of food consumption in 17 country clusters, in conjunction with the reported measurements of total and inorganic arsenic in different foods. We estimated cancer potency factors for arsenic related bladder and lung cancers, and from US Environmental Protection Agency risk estimates for skin cancer to calculate the cancer incidence in males and females within each of the WHO member states. Summary relative risk estimates and population attributable fractions were developed to estimate the YLD, YLL, and DALYs for arsenic-induced CHD. The findings indicate that, globally, each year the combined DALYs for all cancers attributable to inorganic arsenic in food are approximately 1.4 million with variation in global distribution based on population and food consumption patterns. The global burden of CHD attributable to foodborne inorganic arsenic also varied with WHO region and may contribute as much as 49 million DALYs. However, in contrast to cancer burden, there is a threshold effect for arsenic-associated CHD with no increased risk of heart disease at the expected lower bound of arsenic consumption in food. These estimates indicate that foodborne arsenic exposure causes a significant yet avoidable global burden of human disease.

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.

Country-specific estimates of the incidence of intellectual disability associated with prenatal exposure to methylmercury.

This paper describes country-specific estimates of the incidence of intellectual disability in children associated with prenatal exposure to methylmercury. A systematic review was undertaken to identify country-specific data on hair mercury concentrations in women of reproductive age. A variety of approaches were used to estimate biomarker concentrations for countries lacking such data. A dose-effect relationship derived on the basis of the data from three large prospective studies relating prenatal methylmercury exposure to IQ in children was used to estimate the country-specific incidences of mild, moderate, severe, and profound intellectual disability in children as a result of prenatal methylmercury exposure. The incidence of methylmercury-associated mild intellectual disability (IQ scores 50-70) varied nearly 40-fold across countries, with the greatest incidences generally in countries that are islands or that are coastal. Countries with high birth rates and greater consumption of foods that contribute most to methylmercury intake in humans (seafood, rice) can be expected to make the largest contributions to the worldwide burden of disease associated with methylmercury. The assumptions and limitations of the estimates are discussed.

World Health Organization Estimates of the Relative Contributions of Food to the Burden of Disease Due to Selected Foodborne Hazards: A Structured Expert Elicitation.

BACKGROUND: The Foodborne Disease Burden Epidemiology Reference Group (FERG) was established in 2007 by the World Health Organization (WHO) to estimate the global burden of foodborne diseases (FBDs). This estimation is complicated because most of the hazards causing FBD are not transmitted solely by food; most have several potential exposure routes consisting of transmission from animals, by humans, and via environmental routes including water. This paper describes an expert elicitation study conducted by the FERG Source Attribution Task Force to estimate the relative contribution of food to the global burden of diseases commonly transmitted through the consumption of food. METHODS AND FINDINGS: We applied structured expert judgment using Cooke's Classical Model to obtain estimates for 14 subregions for the relative contributions of different transmission pathways for eleven diarrheal diseases, seven other infectious diseases and one chemical (lead). Experts were identified through international networks followed by social network sampling. Final selection of experts was based on their experience including international working experience. Enrolled experts were scored on their ability to judge uncertainty accurately and informatively using a series of subject-matter specific 'seed' questions whose answers are unknown to the experts at the time they are interviewed. Trained facilitators elicited the 5th, and 50th and 95th percentile responses to seed questions through telephone interviews. Cooke's Classical Model uses responses to the seed questions to weigh and aggregate expert responses. After this interview, the experts were asked to provide 5th, 50th, and 95th percentile estimates for the 'target' questions regarding disease transmission routes. A total of 72 experts were enrolled in the study. Ten panels were global, meaning that the experts should provide estimates for all 14 subregions, whereas the nine panels were subregional, with experts providing estimates for one or more subregions, depending on their experience in the region. The size of the 19 hazard-specific panels ranged from 6 to 15 persons with several experts serving on more than one panel. Pathogens with animal reservoirs (e.g. non-typhoidal Salmonella spp. and Toxoplasma gondii) were in general assessed by the experts to have a higher proportion of illnesses attributable to food than pathogens with mainly a human reservoir, where human-to-human transmission (e.g. Shigella spp. and Norovirus) or waterborne transmission (e.g. Salmonella Typhi and Vibrio cholerae) were judged to dominate. For many pathogens, the foodborne route was assessed relatively more important in developed subregions than in developing subregions. The main exposure routes for lead varied across subregions, with the foodborne route being assessed most important only in two subregions of the European region. CONCLUSIONS: For the first time, we present worldwide estimates of the proportion of specific diseases attributable to food and other major transmission routes. These findings are essential for global burden of FBD estimates. While gaps exist, we believe the estimates presented here are the best current source of guidance to support decision makers when allocating resources for control and intervention, and for future research initiatives.

Methodological Framework for World Health Organization Estimates of the Global Burden of Foodborne Disease.

BACKGROUND: The Foodborne Disease Burden Epidemiology Reference Group (FERG) was established in 2007 by the World Health Organization to estimate the global burden of foodborne diseases (FBDs). This paper describes the methodological framework developed by FERG's Computational Task Force to transform epidemiological information into FBD burden estimates. METHODS AND FINDINGS: The global and regional burden of 31 FBDs was quantified, along with limited estimates for 5 other FBDs, using Disability-Adjusted Life Years in a hazard- and incidence-based approach. To accomplish this task, the following workflow was defined: outline of disease models and collection of epidemiological data; design and completion of a database template; development of an imputation model; identification of disability weights; probabilistic burden assessment; and estimating the proportion of the disease burden by each hazard that is attributable to exposure by food (i.e., source attribution). All computations were performed in R and the different functions were compiled in the R package 'FERG'. Traceability and transparency were ensured by sharing results and methods in an interactive way with all FERG members throughout the process. CONCLUSIONS: We developed a comprehensive framework for estimating the global burden of FBDs, in which methodological simplicity and transparency were key elements. All the tools developed have been made available and can be translated into a user-friendly national toolkit for studying and monitoring food safety at the local level.

World Health Organization Global Estimates and Regional Comparisons of the Burden of Foodborne Disease in 2010.

Illness and death from diseases caused by contaminated food are a constant threat to public health and a significant impediment to socio-economic development worldwide. To measure the global and regional burden of foodborne disease (FBD), the World Health Organization (WHO) established the Foodborne Disease Burden Epidemiology Reference Group (FERG), which here reports their first estimates of the incidence, mortality, and disease burden due to 31 foodborne hazards. We find that the global burden of FBD is comparable to those of the major infectious diseases, HIV/AIDS, malaria and tuberculosis. The most frequent causes of foodborne illness were diarrheal disease agents, particularly norovirus and Campylobacter spp. Diarrheal disease agents, especially non-typhoidal Salmonella enterica, were also responsible for the majority of deaths due to FBD. Other major causes of FBD deaths were Salmonella Typhi, Taenia solium and hepatitis A virus. The global burden of FBD caused by the 31 hazards in 2010 was 33 million Disability Adjusted Life Years (DALYs); children under five years old bore 40% of this burden. The 14 subregions, defined on the basis of child and adult mortality, had considerably different burdens of FBD, with the greatest falling on the subregions in Africa, followed by the subregions in South-East Asia and the Eastern Mediterranean D subregion. Some hazards, such as non-typhoidal S. enterica, were important causes of FBD in all regions of the world, whereas others, such as certain parasitic helminths, were highly localised. Thus, the burden of FBD is borne particularly by children under five years old-although they represent only 9% of the global population-and people living in low-income regions of the world. These estimates are conservative, i.e., underestimates rather than overestimates; further studies are needed to address the data gaps and limitations of the study. Nevertheless, all stakeholders can contribute to improvements in food safety throughout the food chain by incorporating these estimates into policy development at national and international levels.

Aldrin and dieldrin: a reevaluation of the cancer and noncancer dose-response assessments.

The dose-response analyses of cancer and noncancer health effects of aldrin and dieldrin were evaluated using current methodology, including benchmark dose analysis and the current U.S. Environmental Protection Agency (U.S. EPA) guidance on body weight scaling and uncertainty factors. A literature review was performed to determine the most appropriate adverse effect endpoints. Using current methodology and information, the estimated reference dose values were 0.0001 and 0.00008 mg/kg-day for aldrin and dieldrin, respectively. The estimated cancer slope factors for aldrin and dieldrin were 3.4 and 7.0 (mg/kg-day)(-1), respectively (i.e., about 5- and 2.3-fold lower risk than the 1987 U.S. EPA assessments). Because aldrin and dieldrin are no longer used as pesticides in the United States, they are presumed to be a low priority for additional review by the U.S. EPA. However, because they are persistent and still detected in environmental samples, quantitative risk assessments based on the best available methods are required. Recent epidemiologic studies do not demonstrate a causal association between aldrin and dieldrin and human cancer risk. The proposed reevaluations suggest that these two compounds pose a lower human health risk than currently reported by the U.S. EPA.

Hexavalent chromium and lung cancer in the chromate industry: a quantitative risk assessment.

The purpose of this investigation was to estimate excess lifetime risk of lung cancer death resulting from occupational exposure to hexavalent-chromium-containing dusts and mists. The mortality experience in a previously studied cohort of 2,357 chromate chemical production workers with 122 lung cancer deaths was analyzed with Poisson regression methods. Extensive records of air samples evaluated for water-soluble total hexavalent chromium were available for the entire employment history of this cohort. Six different models of exposure-response for hexavalent chromium were evaluated by comparing deviances and inspection of cubic splines. Smoking (pack-years) imputed from cigarette use at hire was included in the model. Lifetime risks of lung cancer death from exposure to hexavalent chromium (assuming up to 45 years of exposure) were estimated using an actuarial calculation that accounts for competing causes of death. A linear relative rate model gave a good and readily interpretable fit to the data. The estimated rate ratio for 1 mg/m3-yr of cumulative exposure to hexavalent chromium (as CrO3), with a lag of five years, was RR=2.44 (95% CI=1.54-3.83). The excess lifetime risk of lung cancer death from exposure to hexavalent chromium at the current OSHA permissible exposure limit (PEL) (0.10 mg/m3) was estimated to be 255 per 1,000 (95% CI: 109-416). This estimate is comparable to previous estimates by U.S. EPA, California EPA, and OSHA using different occupational data. Our analysis predicts that current occupational standards for hexavalent chromium permit a lifetime excess risk of dying of lung cancer that exceeds 1 in 10, which is consistent with previous risk assessments.