Paired Liver:Plasma PFAS Concentration Ratios from Adolescents in the Teen-LABS Study and Derivation of Empirical and Mass Balance Models to Predict and Explain Liver PFAS Accumulation.

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

Estimated exposure to perfluoroalkyl substances during infancy and serum-adipokine concentrations in later childhood.

BACKGROUND: Perfluoroalkyl substances (PFASs) are transferred through human milk and may cause elevated exposure during infancy. Given the lack of early postnatal blood samples, PFAS concentrations can be estimated to serve as predictors of subsequent metabolic toxicity. METHODS: A total of 298 children from a prospective birth cohort were followed up through to age 9 years. Serum-PFAS was measured at birth and 18 months of age, while exposures during infancy were estimated by structural equations. Adiponectin, resistin, leptin, and the leptin receptor were measured in serum at age 9. Adjusted regression coefficients for estimated serum-PFAS concentrations were calculated, with additional consideration of the duration of breastfeeding and potential effect modification by sex. RESULTS: A doubling in estimated serum-PFAS concentrations, particularly at ages 6 and 12 months, was associated with a loss of about 10-15% in age 9 resistin concentrations, while other associations were much weaker. Sex dependence of the associations was not observed, and neither did the duration of breastfeeding affect outcomes at age 9. CONCLUSION: Lowered serum-resistin concentrations at age 9 years were most strongly associated with early postnatal PFAS exposures. These findings suggest that infancy may represent a vulnerable time window for some aspects of metabolic programming that may be affected by PFAS exposure. IMPACT: Serum-PFAS concentrations during infancy can be estimated in the absence of blood samples. Adipokine concentrations were measured at age 9 years as metabolic biomarkers. Resistin was significantly lower in children with elevated PFAS exposures in infancy. The findings suggest that early postnatal PFAS exposures may affect subsequent metabolic health. Assessment of infancy vulnerability to PFAS can be explored using estimated serum-PFAS concentrations.

Reference intervals for trace elements in the general Danish population and their dependence on serum proteins.

Reference intervals that indicate the anticipated results of clinical chemistry parameters in a healthy background population are essential for the proper interpretation of laboratory data. In the present study, we analysed major trace elements in blood samples from 400 randomly selected members of the general Danish population. Reference intervals were established for trace elements in both whole blood and serum, and associations with major plasma transport proteins were investigated. In the case of a statistically significant correlation, a corresponding protein-adjusted reference interval was established for comparison with the unadjusted interval. While several trace elements correlated with albumin, ferritin and transferrin, the overall impact of transport proteins was minor and resulted in only marginal changes in the reference intervals. In conclusion, the updated reference intervals for trace elements can be employed without adjusting for plasma protein concentrations.

Human milk extracellular vesicle miRNA expression and associations with maternal characteristics in a population-based cohort from the Faroe Islands.

Human milk plays a critical role in infant development and health, particularly in cognitive, immune, and cardiometabolic functions. Milk contains extracellular vesicles (EVs) that can transport biologically relevant cargo from mother to infant, including microRNAs (miRNAs). We aimed to characterize milk EV-miRNA profiles in a human population cohort, assess potential pathways and ontology, and investigate associations with maternal characteristics. We conducted the first study to describe the EV miRNA profile of human milk in 364 mothers from a population-based mother-infant cohort in the Faroe Islands using small RNA sequencing. We detected 1523 miRNAs with ≥ one read in 70% of samples. Using hierarchical clustering, we determined five EV-miRNA clusters, the top three consisting of 15, 27 and 67 miRNAs. Correlation coefficients indicated that the expression of many miRNAs within the top three clusters was highly correlated. Top-cluster human milk EV-miRNAs were involved in pathways enriched for the endocrine system, cellular community, neurodevelopment, and cancers. miRNA expression was associated with time to milk collection post-delivery, maternal body mass index, and maternal smoking, but not maternal parity. Future studies investigating determinants of human EV-miRNAs and associated health outcomes are needed to elucidate the role of human milk EV-miRNAs in health and disease.

Human Health and Ocean Pollution.

Background: Pollution - unwanted waste released to air, water, and land by human activity - is the largest environmental cause of disease in the world today. It is responsible for an estimated nine million premature deaths per year, enormous economic losses, erosion of human capital, and degradation of ecosystems. Ocean pollution is an important, but insufficiently recognized and inadequately controlled component of global pollution. It poses serious threats to human health and well-being. The nature and magnitude of these impacts are only beginning to be understood. Goals: (1) Broadly examine the known and potential impacts of ocean pollution on human health. (2) Inform policy makers, government leaders, international organizations, civil society, and the global public of these threats. (3) Propose priorities for interventions to control and prevent pollution of the seas and safeguard human health. Methods: Topic-focused reviews that examine the effects of ocean pollution on human health, identify gaps in knowledge, project future trends, and offer evidence-based guidance for effective intervention. Environmental Findings: Pollution of the oceans is widespread, worsening, and in most countries poorly controlled. It is a complex mixture of toxic metals, plastics, manufactured chemicals, petroleum, urban and industrial wastes, pesticides, fertilizers, pharmaceutical chemicals, agricultural runoff, and sewage. More than 80% arises from land-based sources. It reaches the oceans through rivers, runoff, atmospheric deposition and direct discharges. It is often heaviest near the coasts and most highly concentrated along the coasts of low- and middle-income countries. Plastic is a rapidly increasing and highly visible component of ocean pollution, and an estimated 10 million metric tons of plastic waste enter the seas each year. Mercury is the metal pollutant of greatest concern in the oceans; it is released from two main sources - coal combustion and small-scale gold mining. Global spread of industrialized agriculture with increasing use of chemical fertilizer leads to extension of Harmful Algal Blooms (HABs) to previously unaffected regions. Chemical pollutants are ubiquitous and contaminate seas and marine organisms from the high Arctic to the abyssal depths. Ecosystem Findings: Ocean pollution has multiple negative impacts on marine ecosystems, and these impacts are exacerbated by global climate change. Petroleum-based pollutants reduce photosynthesis in marine microorganisms that generate oxygen. Increasing absorption of carbon dioxide into the seas causes ocean acidification, which destroys coral reefs, impairs shellfish development, dissolves calcium-containing microorganisms at the base of the marine food web, and increases the toxicity of some pollutants. Plastic pollution threatens marine mammals, fish, and seabirds and accumulates in large mid-ocean gyres. It breaks down into microplastic and nanoplastic particles containing multiple manufactured chemicals that can enter the tissues of marine organisms, including species consumed by humans. Industrial releases, runoff, and sewage increase frequency and severity of HABs, bacterial pollution, and anti-microbial resistance. Pollution and sea surface warming are triggering poleward migration of dangerous pathogens such as the Vibrio species. Industrial discharges, pharmaceutical wastes, pesticides, and sewage contribute to global declines in fish stocks. Human Health Findings: Methylmercury and PCBs are the ocean pollutants whose human health effects are best understood. Exposures of infants in utero to these pollutants through maternal consumption of contaminated seafood can damage developing brains, reduce IQ and increase children's risks for autism, ADHD and learning disorders. Adult exposures to methylmercury increase risks for cardiovascular disease and dementia. Manufactured chemicals - phthalates, bisphenol A, flame retardants, and perfluorinated chemicals, many of them released into the seas from plastic waste - can disrupt endocrine signaling, reduce male fertility, damage the nervous system, and increase risk of cancer. HABs produce potent toxins that accumulate in fish and shellfish. When ingested, these toxins can cause severe neurological impairment and rapid death. HAB toxins can also become airborne and cause respiratory disease. Pathogenic marine bacteria cause gastrointestinal diseases and deep wound infections. With climate change and increasing pollution, risk is high that Vibrio infections, including cholera, will increase in frequency and extend to new areas. All of the health impacts of ocean pollution fall disproportionately on vulnerable populations in the Global South - environmental injustice on a planetary scale. Conclusions: Ocean pollution is a global problem. It arises from multiple sources and crosses national boundaries. It is the consequence of reckless, shortsighted, and unsustainable exploitation of the earth's resources. It endangers marine ecosystems. It impedes the production of atmospheric oxygen. Its threats to human health are great and growing, but still incompletely understood. Its economic costs are only beginning to be counted.Ocean pollution can be prevented. Like all forms of pollution, ocean pollution can be controlled by deploying data-driven strategies based on law, policy, technology, and enforcement that target priority pollution sources. Many countries have used these tools to control air and water pollution and are now applying them to ocean pollution. Successes achieved to date demonstrate that broader control is feasible. Heavily polluted harbors have been cleaned, estuaries rejuvenated, and coral reefs restored.Prevention of ocean pollution creates many benefits. It boosts economies, increases tourism, helps restore fisheries, and improves human health and well-being. It advances the Sustainable Development Goals (SDG). These benefits will last for centuries. Recommendations: World leaders who recognize the gravity of ocean pollution, acknowledge its growing dangers, engage civil society and the global public, and take bold, evidence-based action to stop pollution at source will be critical to preventing ocean pollution and safeguarding human health.Prevention of pollution from land-based sources is key. Eliminating coal combustion and banning all uses of mercury will reduce mercury pollution. Bans on single-use plastic and better management of plastic waste reduce plastic pollution. Bans on persistent organic pollutants (POPs) have reduced pollution by PCBs and DDT. Control of industrial discharges, treatment of sewage, and reduced applications of fertilizers have mitigated coastal pollution and are reducing frequency of HABs. National, regional and international marine pollution control programs that are adequately funded and backed by strong enforcement have been shown to be effective. Robust monitoring is essential to track progress.Further interventions that hold great promise include wide-scale transition to renewable fuels; transition to a circular economy that creates little waste and focuses on equity rather than on endless growth; embracing the principles of green chemistry; and building scientific capacity in all countries.Designation of Marine Protected Areas (MPAs) will safeguard critical ecosystems, protect vulnerable fish stocks, and enhance human health and well-being. Creation of MPAs is an important manifestation of national and international commitment to protecting the health of the seas.

Perfluorinated substances, risk factors for multiple sclerosis and cellular immune activation.

Perfluorinated alkylated substances (PFASs) have immunomodulatory effects but the impact on multiple sclerosis (MS) and cellular immune functions is only sparsely described. In the present study, we found lower concentrations of the long chain PFAS perfluorooctane sulfonic acid (PFOS) in MS than in healthy controls (HC). In HC, we did not detect associations between PFOS concentrations and immune phenotypes. Analyzing the impact of known MS risk factors on cellular immune functions, we found that smoking and Epstein-Barr nuclear antigen 1 antibodies were associated with distinct circulating immune cell changes. In summary, current background PFAS exposure is not an important risk factor for MS.

Safety of Safety Evaluation of Pesticides: developmental neurotoxicity of chlorpyrifos and chlorpyrifos-methyl.

Authorization of pesticides for market release requires toxicity testing on animals, typically performed by test laboratories on contract with the pesticide producer. The latter provides the results and summary to the regulatory authorities. For the commonly used pesticide chlorpyrifos, an industry-funded toxicity study concludes that no selective effects on neurodevelopment occur even at high exposures. In contrast, the evidence from independent studies points to adverse effects of current exposures on cognitive development in children. We reviewed the industry-funded developmental neurotoxicity test data on chlorpyrifos and the related substance chlorpyrifos-methyl. We noted treatment-related changes in a brain dimension measure for chlorpyrifos at all dose levels tested, although not been reported in the original test summary. We further found issues which inappropriately decrease the ability of the studies to reveal true effects, including a dosage regimen that resulted in too low exposure of the nursing pups for chlorpyrifos and possibly for chlorpyrifos-methyl, and a failure to detect any neurobehavioral effects of lead nitrate used as positive control in the chlorpyrifos study. Our observations thus suggest that conclusions in test reports submitted by the producer may be misleading. This discrepancy affects the ability of regulatory authorities to perform a valid and safe evaluation of these pesticides. The difference between raw data and conclusions in the test reports indicates a potential existence of bias that would require regulatory attention and possible resolution.

Identification of sex-specific DNA methylation changes driven by specific chemicals in cord blood in a Faroese birth cohort.

Faroe islanders consume marine foods contaminated with methylmercury (MeHg), polychlorinated biphenyls (PCBs), and other toxicants associated with chronic disease risks. Differential DNA methylation at specific CpG sites in cord blood may serve as a surrogate biomarker of health impacts from chemical exposures. We aimed to identify key environmental chemicals in cord blood associated with DNA methylation changes in a population with elevated exposure to chemical mixtures. We studied 72 participants of a Faroese birth cohort recruited between 1986 and 1987 and followed until adulthood. The cord blood DNA methylome was profiled using Infinium HumanMethylation450 BeadChips. We determined the associations of CpG site changes with concentrations of MeHg, major PCBs, other organochlorine compounds [hexachlorobenzene (HCB), p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE) and p,p'-dichlorodiphenyltrichloroethane], and perfluoroalkyl substances. In a combined sex analysis, among the 16 chemicals studied, PCB congener 105 (CB-105) exposure was associated with the majority of differentially methylated CpG sites (214 out of a total of 250). In female-only analysis, only 73 CB-105 associated CpG sites were detected, 44 of which were mapped to genes in the ELAV1-associated cancer network. In males-only, methylation changes were seen for perfluorooctane sulfonate, HCB, and p,p'-DDE in 10,598, 1,238, and 1,473 CpG sites, respectively, 15% of which were enriched in cytobands of the X-chromosome associated with neurological disorders. In this multiple-pollutant and genome-wide study, we identified key epigenetic toxicants. The significant enrichment of specific X-chromosome sites in males implies potential sex-specific epigenome responses to prenatal chemical exposures.

Plasma Concentrations of Perfluoroalkyl Substances and Risk of Type 2 Diabetes: A Prospective Investigation among U.S. Women.

BACKGROUND: Emerging evidence suggests that perfluoroalkyl substances (PFASs) are endocrine disruptors and may contribute to the etiology of type 2 diabetes (T2D), but this hypothesis needs to be clarified in prospective human studies. OBJECTIVES: Our objective was to examine the associations between PFAS exposures and subsequent incidence of T2D in the Nurses' Health Study II (NHSII). In addition, we aimed to evaluate potential demographic and lifestyle determinants of plasma PFAS concentrations. METHODS: A prospective nested case-control study of T2D was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in 1995-2000 [(mean±SD): 45.3±4.4 y) of age]. We identified and ascertained 793 incident T2D cases through 2011 (mean±SD) years of follow-up: 6.7±3.7 y). Each case was individually matched to a control (on age, month and fasting status at sample collection, and menopausal status and hormone replacement therapy). Plasma concentrations of five major PFASs, including perfluorooctanesulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexanesulfonate, perfluorononanoic acid, and perfluorodecanoic acid were measured. Odds ratios (ORs) of T2D by PFAS tertiles were estimated by conditional logistic regression. RESULTS: Shorter breastfeeding duration and higher intake of certain foods, such as seafood and popcorn, were significantly associated with higher plasma concentrations of PFASs among controls. After multivariate adjustment for T2D risk factors, including body mass index, family history, physical activity, and other covariates, higher plasma concentrations of PFOS and PFOA were associated with an elevated risk of T2D. Comparing extreme tertiles of PFOS or PFOA, ORs were 1.62 (95% CI: 1.09, 2.41; ptrend=0.02) and 1.54 (95% CI: 1.04, 2.28; ptrend=0.03), respectively. Other PFASs were not clearly associated with T2D risk. CONCLUSIONS: Background exposures to PFASs in the late 1990s were associated with higher T2D risk during the following years in a prospective case-control study of women from the NHSII. These findings support a potential diabetogenic effect of PFAS exposures. https://doi.org/10.1289/EHP2619.

Health effects associated with measured levels of contaminants in the Arctic.

The Human Health Assessment Group has over the past decade recommended that effect studies be conducted in the circumpolar area. Such studies examine the association between contaminant exposure in the Arctic populations and health effects. Because foetuses and young children are the most vulnerable, effect studies are often prospective child cohort studies. The emphasis in this article is on a description of the effects associated with contaminant exposure in the Arctic. The main topics addressed are neurobehavioural, immunological, reproductive, cardiovascular, endocrine and carcinogenic effect. For each topic, the association between exposure and effects is described, and some results are reported for similar studies outside the Arctic.

Umbilical Cord Serum 25-Hydroxyvitamin D Concentrations and Relation to Birthweight, Head Circumference and Infant Length at Age 14 Days.

BACKGROUND: Insufficient supply of vitamin D during early development may negatively affect offspring growth. METHODS: We examined the association between umbilical cord (UC) serum 25-hydroxyvitamin D (25(OH)D) concentrations and infant size in a study of two Faroese birth cohorts of 1038 singleton infants. In the third trimester, the pregnant women completed questionnaires, and clinical examination included birthweight, head circumference, and infant length at age 14 days. RESULTS: Fifty-three percent of the newborn population had UC 25(OH)D < 25 nmol/L as determined by LC-MS/MS. Using multiple linear regression models with adjustment for pre-pregnancy BMI, sex, parity, gestational age, or infant age at examination, season of birth, smoking, gestational diabetes, examiner, and cohort identity, we found no relationship between birthweight or head circumference and UC 25(OH)D. However, infants with vitamin D status <12 nmol/L had a 0.49 (95% confidence interval 0.05, 0.93) cm lower length than infants with vitamin D status >50 nmol/L in models further adjusted for birthweight. CONCLUSION: Our data suggest that umbilical cord serum 25(OH)D concentrations are positively associated with infant length but not with birthweight and head circumference. Although the paediatric relevance of the observed association is unclear, the possible long-term consequences of late-pregnancy hypovitaminosis D deserve attention.

Associations between plasma concentrations of PCB 28 and possible indoor exposure sources in Danish school children and mothers.

BACKGROUND: Polychlorinated biphenyls (PCBs) are ubiquitously present in the environment and are suspected of carcinogenic, neurotoxic and immunotoxic effects. Significantly higher plasma concentrations of the congener PCB 28 occur in children compared to adults. Exposure in schools may contribute to this difference. OBJECTIVE: To determine whether increased blood plasma concentrations of PCB 28 in Danish school children and mothers are associated with living in homes or attending schools constructed in the PCB period (1959-1977). METHODS: PCB 28 was analyzed in plasma samples from 116 children aged 6-11years and 143 mothers living in an urban and a rural area in Denmark and participating in the European pilot project DEMOCOPHES (Demonstration of a study to COordinate and Perform Human Biomonitoring on a European Scale). In Denmark, PCBs were used in construction in the period 1950-1977, and year of construction or renovation of the homes and schools was used as a proxy for indoor PCB exposure. Linear regression models were used to assess the association between potential PCB exposure from building materials and lipid adjusted concentrations of PCB 28 in plasma, with and without adjustment for potential confounders. RESULTS: Among the 116 children and 143 mothers, we were able to specify home construction period in all but 4 children and 5 mothers leaving 111 children and 138 mothers for our analyses. The median lipid adjusted plasma PCB 28 concentration was 3 (range: 1-28) ng/g lipid in the children and 2 (range: 1-8) ng/g lipid in the mothers. Children living in homes built in the PCB period had significantly higher lipid adjusted plasma PCB 28 concentrations compared to children living in homes built before or after the PCB period. Following adjustment for covariates, PCB 28 concentrations in children were 40 (95% CI: 13; 68) percent higher than concentrations of children living in homes constructed at other times. Furthermore, children attending schools built or substantially refurbished in the PCB period also had significantly higher (46%, 95% CI: 22; 70) PCB 28 concentrations compared to children attending schools constructed before or after the PCB period, while their mothers had similar concentrations. Adjustment for the most prevalent congener, PCB 153, did not change this effect of home or school construction. When both home and school construction year were included in the models, the increase in lipid adjusted plasma PCB 28 for children living in or attending schools from the PCB period was no longer statistically significant. The individual effect of home and school construction periods could not be evaluated further with the available data. CONCLUSION: Our results suggest that PCB exposure in the indoor environment in schools and homes constructed during the PCB period may contribute significantly to children's plasma PCB 28 concentration. Efforts to minimize PCB exposure in indoor environments should be considered.

Circulating persistent organic pollutants and body fat distribution: Evidence from NHANES 1999-2004.

OBJECTIVE: To evaluate and compare the correlations of various circulating persistent organic pollutants (POPs) with fat mass percentages (FM%) of trunk, leg, and whole body measured by dual-energy X-ray absorptiometry. METHODS: This study included 2358 adults (≥20 years) in the National Health and Nutrition Examination Survey 1999-2004. Partial Pearson correlation coefficients were calculated, after adjusting for major confounders, including age, smoking status, and history of lactation and parity. Wolfe's method was used to compare correlation coefficients derived from the same participants. RESULTS: Twelve POPs showed significantly different correlations with fat depots in trunk and leg regions. ß-hexachlorocyclohexane, heptachlorodibenzo-p-dioxin, octachlorodibenzo-p-dioxin, and polychlorinated biphenyl (PCB)-126 showed stronger positive correlations with trunk FM% than with leg FM%, whereas PCBs with ≥6 chlorines were more inversely correlated with trunk FM% than leg FM%. Age-stratified analysis showed stronger inverse correlations between POPs and trunk FM% mainly in participants <40 years, whereas stronger positive correlations between POPs and trunk FM% were observed in older participants. CONCLUSIONS: Stronger associations between POPs and trunk fat as compared to leg fat possibly indicated a more important role of trunk fat in the pharmacokinetics of POPs, or a stronger effect of POPs, as endocrine disruptors, on trunk fat metabolism.

Perfluorinated Alkyl Substances: Emerging Insights Into Health Risks.

Perfluorinated alkyl substances have been in use for over sixty years. These highly stable substances were at first thought to be virtually inert and of low toxicity. Toxicity information slowly emerged on perfluorooctanoic acid and perfluorooctane sulfonate. More than thirty years ago, early studies reported immunotoxicity and carcinogenicity effects. The substances were discovered in blood samples from exposed workers, then in the general population and in community water supplies near U.S. manufacturing plants. Only recently has research publication on perfluorooctanoic acid and perfluorooctane sulfonate intensified. While the toxicology database is still far from complete, carcinogenicity and immunotoxicity now appear to be relevant risks at prevalent exposure levels. Existing drinking water limits are based on less complete evidence that was available before 2008 and may be more than 100-fold too high. As risk evaluations assume that untested effects do not require regulatory attention, the greatly underestimated health risks from perfluorooctanoic acid and perfluorooctane sulfonate illustrate the public health implications of assuming the safety of incompletely tested industrial chemicals.

IARC monographs: 40 years of evaluating carcinogenic hazards to humans.

BACKGROUND: Recently, the International Agency for Research on Cancer (IARC) Programme for the Evaluation of Carcinogenic Risks to Humans has been criticized for several of its evaluations, and also for the approach used to perform these evaluations. Some critics have claimed that failures of IARC Working Groups to recognize study weaknesses and biases of Working Group members have led to inappropriate classification of a number of agents as carcinogenic to humans. OBJECTIVES: The authors of this Commentary are scientists from various disciplines relevant to the identification and hazard evaluation of human carcinogens. We examined criticisms of the IARC classification process to determine the validity of these concerns. Here, we present the results of that examination, review the history of IARC evaluations, and describe how the IARC evaluations are performed. DISCUSSION: We concluded that these recent criticisms are unconvincing. The procedures employed by IARC to assemble Working Groups of scientists from the various disciplines and the techniques followed to review the literature and perform hazard assessment of various agents provide a balanced evaluation and an appropriate indication of the weight of the evidence. Some disagreement by individual scientists to some evaluations is not evidence of process failure. The review process has been modified over time and will undoubtedly be altered in the future to improve the process. Any process can in theory be improved, and we would support continued review and improvement of the IARC processes. This does not mean, however, that the current procedures are flawed. CONCLUSIONS: The IARC Monographs have made, and continue to make, major contributions to the scientific underpinning for societal actions to improve the public's health.

Occupational pesticide exposure in early pregnancy associated with sex-specific neurobehavioral deficits in the children at school age.

Prenatal exposure to pesticides may affect neurodevelopment, while the impact of modern pesticides is unclear. From 1997-2001, women working in greenhouse horticultures were recruited at the beginning of their pregnancy. Based on detailed interview of the women and their employers, those categorized as occupationally exposed to pesticides were moved to unexposed work functions or went on paid leave, while women without any exposure were considered unexposed controls. Of the resulting birth cohort of 203 children, 133 (65%) were examined at age 6 to 11 years together with 44 newly recruited children of same age whose mothers were not occupationally exposed to pesticides in pregnancy. All children underwent a standardized examination including a battery of neurodevelopmental tests. Maternal occupational pesticide exposure in early pregnancy was associated with prolonged brainstem auditory evoked potential latencies in the children as a whole and with impaired neuropsychological function in girls, while no effect was apparent in boys. In girls, language and motor speed functions were significantly inversely associated with prenatal exposure, and a non-significant tendency toward decreased function was also seen for other neuropsychological outcomes. A structural equation model that combined all these test results showed an overall impaired neuropsychological function in girls prenatally exposed to pesticides. Thus, our findings suggest an adverse effect of maternal occupational pesticide exposure on their children's neurodevelopment, despite the fact that the exposures occurred solely during early pregnancy and under well regulated working conditions, where special measures to protect pregnant women were applied.

Iron status as a covariate in methylmercury-associated neurotoxicity risk.

Intrauterine methylmercury exposure and prenatal iron deficiency negatively affect offspring's brain development. Since fish is a major source of both methylmercury and iron, occurrence of negative confounding may affect the interpretation of studies concerning cognition. We assessed relationships between methylmercury exposure and iron-status in childbearing females from a population naturally exposed to methylmercury through fish intake (Amazon). We concluded a census (refuse <20%) collecting samples from 274 healthy females (12-49 years) for hair-mercury determination and assessed iron-status through red cell tests and determination of serum ferritin and iron. Reactive C protein and thyroid hormones was used for excluding inflammation and severe thyroid dysfunctions that could affect results. We assessed the association between iron-status and hair-mercury by bivariate correlation analysis and also by different multivariate models: linear regression (to check trends); hierarchical agglomerative clustering method (groups of variables correlated with each other); and factor analysis (to examine redundancy or duplication from a set of correlated variables). Hair-mercury correlated weakly with mean corpuscular volume (r=.141; P=.020) and corpuscular hemoglobin (r=.132; .029), but not with the best biomarker of iron-status, ferritin (r=.037; P=.545). In the linear regression analysis, methylmercury exposure showed weak association with age-adjusted ferritin; age had a significant coefficient (Beta=.015; 95% CI: .003-.027; P=.016) but ferritin did not (Beta=.034; 95% CI: -.147 to .216; P=.711). In the hierarchical agglomerative clustering method, hair-mercury and iron-status showed the smallest similarities. Regarding factor analysis, iron-status and hair-mercury loaded different uncorrelated components. We concluded that iron-status and methylmercury exposure probably occur in an independent way.

What are the toxicological effects of mercury in Arctic biota?

This review critically evaluates the available mercury (Hg) data in Arctic marine biota and the Inuit population against toxicity threshold values. In particular marine top predators exhibit concentrations of mercury in their tissues and organs that are believed to exceed thresholds for biological effects. Species whose concentrations exceed threshold values include the polar bears (Ursus maritimus), beluga whale (Delphinapterus leucas), pilot whale (Globicephala melas), hooded seal (Cystophora cristata), a few seabird species, and landlocked Arctic char (Salvelinus alpinus). Toothed whales appear to be one of the most vulnerable groups, with high concentrations of mercury recorded in brain tissue with associated signs of neurochemical effects. Evidence of increasing concentrations in mercury in some biota in Arctic Canada and Greenland is therefore a concern with respect to ecosystem health.