Innovative analytical methodologies for characterizing chemical exposure with a view to next-generation risk assessment.

The chemical burden on the environment and human population is increasing. Consequently, regulatory risk assessment must keep pace to manage, reduce, and prevent adverse impacts on human and environmental health associated with hazardous chemicals. Surveillance of chemicals of known, emerging, or potential future concern, entering the environment-food-human continuum is needed to document the reality of risks posed by chemicals on ecosystem and human health from a one health perspective, feed into early warning systems and support public policies for exposure mitigation provisions and safe and sustainable by design strategies. The use of less-conventional sampling strategies and integration of full-scan, high-resolution mass spectrometry and effect-directed analysis in environmental and human monitoring programmes have the potential to enhance the screening and identification of a wider range of chemicals of known, emerging or potential future concern. Here, we outline the key needs and recommendations identified within the European Partnership for Assessment of Risks from Chemicals (PARC) project for leveraging these innovative methodologies to support the development of next-generation chemical risk assessment.

Assessment of Differentiated Thyroid Carcinomas in French Polynesia After Atmospheric Nuclear Tests Performed by France.

Importance: Due to the amount of iodine 131 released in nuclear tests and its active uptake by the thyroid, differentiated thyroid carcinoma (DTC) is the most serious health risk for the population living near sites of nuclear tests. Whether low doses to the thyroid from nuclear fallout are associated with increased risk of thyroid cancer remains a controversial issue in medicine and public health, and a misunderstanding of this issue may be associated with overdiagnosis of DTCs. Design, Setting, and Participants: This case-control study was conducted by extending a case-control study published in 2010 that included DTCs diagnosed between 1984 and 2003 by adding DTCs diagnosed between 2004 and 2016 and improving the dose assessment methodology. Data on 41 atmospheric nuclear tests conducted by France between 1966 and 1974 in French Polynesia (FP) were assessed from original internal radiation-protection reports, which the French military declassified in 2013 and which included measurements in soil, air, water, milk, and food in all FP archipelagos. These original reports led to an upward reassessment of the nuclear fallout from the tests and a doubling of estimates of the mean thyroid radiation dose received by inhabitants from 2 mGy to nearly 5 mGy. Included patients were diagnosed from 1984 to 2016 with DTC at age 55 years or younger and were born in and resided in FP at diagnosis; 395 of 457 eligible cases were included, and up to 2 controls per case nearest by birthdate and matched on sex were identified from the FP birth registry. Data were analyzed from March 2019 through October 2021. Exposure: The radiation dose to the thyroid gland was estimated using recently declassified original radiation-protection service reports, meteorological reports, self-reported lifestyle information, and group interviews of key informants and female individuals who had children at the time of these tests. Main Outcomes and Measures: The lifetime risk of DTC based on Biological Effects of Ionizing Radiation (BEIR) VII models was estimated. Results: A total of 395 DTC cases (336 females [85.1%]; mean [SD] age at end of follow-up, 43.6 [12.9] years) and 555 controls (473 females [85.2%]; mean [SD] age at end of follow-up, 42.3 [12.5] years) were included. No association was found between thyroid radiation dose received before age 15 years and risk of DTC (excess relative risk [ERR] per milligray, 0.04; 95% CI, -0.09 to 0.17; P = .27). When excluding unifocal noninvasive microcarcinomas, the dose response was significant (ERR per milligray, 0.09; 95% CI, -0.03 to 0.02; P = .02), but several incoherencies with the results of the initial study reduce the credibility of this result. The lifetime risk for the entire FP population was 29 cases of DTC (95% CI, 8-97 cases), or 2.3% (95% CI, 0.6%-7.7%) of 1524 sporadic DTC cases in this population. Conclusions and Relevance: This case-control study found that French nuclear tests were associated with an increase in lifetime risk of PTC in FP residents of 29 cases of PTC. This finding suggests that the number of thyroid cancer cases and the true order of magnitude of health outcomes associated with these nuclear tests were small, which may reassure populations of this Pacific territory.

Update of the risk assessment of nickel in food and drinking water.

The European Commission asked EFSA to update its previous Opinion on nickel in food and drinking water, taking into account new occurrence data, the updated benchmark dose (BMD) Guidance and newly available scientific information. More than 47,000 analytical results on the occurrence of nickel were used for calculating chronic and acute dietary exposure. An increased incidence of post-implantation loss in rats was identified as the critical effect for the risk characterisation of chronic oral exposure and a BMDL 10 of 1.3 mg Ni/kg body weight (bw) per day was selected as the reference point for the establishment of a tolerable daily intake (TDI) of 13 µg/kg bw. Eczematous flare-up reactions in the skin elicited in nickel-sensitised humans, a condition known as systemic contact dermatitis, was identified as the critical effect for the risk characterisation of acute oral exposure. A BMDL could not be derived, and therefore, the lowest-observed-adverse-effect-level of 4.3 µg Ni/kg bw was selected as the reference point. The margin of exposure (MOE) approach was applied and an MOE of 30 or higher was considered as being indicative of a low health concern. The mean lower bound (LB)/upper bound (UB) chronic dietary exposure was below or at the level of the TDI. The 95th percentile LB/UB chronic dietary exposure was below the TDI in adolescents and in all adult age groups, but generally exceeded the TDI in toddlers and in other children, as well as in infants in some surveys. This may raise a health concern in these young age groups. The MOE values for the mean UB acute dietary exposure and for the 95th percentile UB raises a health concern for nickel-sensitised individuals. The MOE values for an acute scenario regarding consumption of a glass of water on an empty stomach do not raise a health concern.

Human dietary exposure to chemicals in sub-Saharan Africa: safety assessment through a total diet study.

BACKGROUND: Human dietary exposure to chemicals can result in a wide range of adverse health effects. Some substances might cause non-communicable diseases, including cancer and coronary heart diseases, and could be nephrotoxic. Food is the main human exposure route for many chemicals. We aimed to assess human dietary exposure to a wide range of food chemicals. METHODS: We did a total diet study in Benin, Cameroon, Mali, and Nigeria. We assessed 4020 representative samples of foods, prepared as consumed, which covered more than 90% of the diet of 7291 households from eight study centres. By combining representative dietary surveys of countries with findings for concentrations of 872 chemicals in foods, we characterised human dietary exposure. FINDINGS: Exposure to lead could result in increases in adult blood pressure up to 2·0 mm Hg, whereas children might lose 8·8-13·3 IQ points (95th percentile in Kano, Nigeria). Morbidity factors caused by coexposure to aflatoxin B1 and hepatitis B virus, and sterigmatocystin and fumonisins, suggest several thousands of additional liver cancer cases per year, and a substantial contribution to the burden of chronic malnutrition in childhood. Exposure to 13 polycyclic aromatic hydrocarbons from consumption of smoked fish and edible oils exceeded levels associated with possible carcinogenicity and genotoxicity health concerns in all study centres. Exposure to aluminium, ochratoxin A, and citrinin indicated a public health concern about nephropathies. From 470 pesticides tested across the four countries, only high concentrations of chlorpyrifos in smoked fish (unauthorised practice identified in Mali) could pose a human health risk. INTERPRETATION: Risks characterised by this total diet study underscore specific priorities in terms of food safety management in sub-Saharan Africa. Similar investigations specifically targeting children are crucially needed. FUNDING: Standards and Trade Development Facility.

Cr(VI) and Cr(III) in milk, dairy and cereal products and dietary exposure assessment.

Milk, dairy and cereal products are the main contributors to total chromium (Cr) dietary exposure in France (up to 42% for children), but there have been no assessments regarding dietary exposure to Cr(VI) or Cr(III) to date. To assess dietary exposure, total chromium and Cr(VI) were determined in 68 different brands and origins of milk, dairy and cereal products. Cr(VI) was not detected in these samples despite the very high sensitivity of the method used. It was therefore assumed that total chromium is only present in the Cr(III) form. Total chromium levels were quantified in 58% of milk and dairy products and 76% of cereal products. The highest mean levels were found in breakfast cereals and cheese (269 and 25 µg Cr /kg fresh weight, respectively). The findings pointed out that the dietary exposure levels of Cr(III) and Cr(VI) were well below the health-based guidance values.

Non-Essential Trace Elements Dietary Exposure in French Polynesia: Intake Assessment, Nail Bio Monitoring and Thyroid Cancer Risk

Background: In French Polynesia, thyroid cancer mortality and incidence is reported to be the highest in the world. Excessive levels of non-essential trace elements (nETE) in the body are associated with several types of cancer. Objective: The present study aims to provide quantitative information on food contamination by mercury (Hg), lead (Pb), arsenic (As) and cadmium (Cd) in French Polynesia and its potential correlation with measurements performed in fingernails of Polynesians, and then to investigate the potential association between these nETE and different thyroid cancer risks. Methods: The study population included 229 interviewed cases and 373 interviewed controls We performed a descriptive analysis of Polynesian food and examined the association between thyroid cancer risk and daily intake levels of nETE and with fingernail nETE levels. Results: Hg contamination was mainly present in sea products, Pb contamination was present in almost all samples, Cd was detectable in starchy food and As was detectable in all sea products. No patient exceeded dietary contamination WHO limits for Pb, 2 participants exceeded it for Hg and 3 individuals (0.5%) for cadmium. In fingernail clippings, the most detectable pollutant was Pb (553 participants), then Hg (543 participants) then Cd (only in 130 participants). Thyroid cancer risk was increased more than 4 times by Pb daily intake in patients with a history of cancer in first-degree relatives than in ones without (p for interaction =0.01), and 2 times more in women with more than 3 pregnancies than in those with none or less (p for interaction =0.005); it was also increased following As intake by more than 30% in patients with a history of cancer in first-degree relatives than in ones without (p for interaction =0.05). Conclusion: Locally produced foods are not a source of nETE exposure in French Polynesia. Dieatry nETE exposure and fingernail nETE concentration are not associated to differentiated thyroid cancer risk. No correlation found between nETE dietary exposure and fingernail nETE concentration.

Dietary exposure to cadmium and health risk assessment in children - Results of the French infant total diet study.

Besides specific occupational activities or smoking, food is the main route of cadmium exposure for the general population. In France a total diet study previously conducted for adults and children over 3 years old revealed that health concerns due to Cd dietary exposure existed for both adults and children. This study showed that the Cd tolerable weekly intake, based on potential nephrotoxicity effects, is exceeded by a high proportion of children under 3 years old. Nephrotoxicity results from the accumulation of cadmium in the kidney and appears typically after long-term exposure (40-50 years). Despite the exceeding of the tolerable weekly intake observed during the first three years of childhood, due to low body weights compared to adults, the accumulation rate of cadmium is much lower during the whole childhood period (from 0 to 17 years of age) than during adulthood. These data suggest that dietary exposure to cadmium should be reduced for both children and adults to prevent health concerns associated with nephrotoxicity in later life. Moreover, recent literature suggests that Cd can induce other adverse health effects (especially endocrine disruption or neurotoxicity) that could be triggered at even lower doses than those triggering nephrotoxicity.

Development and validation of an HPLC-MS/MS method with QuEChERS extraction using isotopic dilution to simultaneously analyze chlordecone and chlordecol in animal livers.

A QuEChERS extraction method followed by HPLC-MS/MS analysis was developed to simultaneously analyze chlordecone and its metabolite chlordecol in animal livers. The overall method was validated with accuracy profiles according to the French Standard NF V03-110 and European Union guidelines. The validation was performed on bovine, ovine and porcine liver samples. Linearity, matrix effect, accuracy, within-laboratory repeatability, specificity, LOQ, Q/q relative ion intensities, and uncertainty were reported. Recoveries were between 70% and 120%. LOQs of 1.36 µg chlordecone kg-1 and 2.50 µg chlordecol kg-1 of fresh liver were found. Twelve contaminated livers of bovine, ovine and porcine origin from the French West Indies or samples from in vivo studies were analyzed. In these liver samples from contaminated animals, chlordecone was quantified at concentrations higher than the maximum residue limit and chlordecol in very low amounts in all the samples. In addition, these results confirm that chlordecone can be metabolized in ruminant species.

Dietary exposure and health risk assessment for 14 toxic and essential trace elements in Yaoundé: the Cameroonian total diet study.

Dietary exposure to trace elements (aluminium, antimony, barium, cadmium, lead, nickel, vanadium, copper, manganese, molybdenum, germanium, lithium, strontium and tellurium) was assessed by the total diet study (TDS) method. Sixty-four pooled samples representing 96.5% of the diet in Yaoundé, Cameroon, were prepared "as consumed" before analysis. Consumption data were sourced from a households' budget survey. Dietary exposures were compared with health-based guidance or nutritional values and to worldwide TDS results. The health-based guidance value was exceeded by ≤ 0.2% of the study population for aluminium, antimony, barium, cadmium, nickel and vanadium. For lead, the observed 95th percentile of exposure (3.05 µg kg(-1) body weight day(-1)) equals the critical value considered by JECFA for cardiovascular effects; therefore, risk to health cannot be excluded for certain consumer groups. The population at risk of excess intake for manganese, copper, molybdenum and nickel was considered to be low (≤ 0.3%). The prevalence of inadequate intake was estimated at 5.9% for copper and was nil for molybdenum. Due to the lack of toxicological and/or nutritional consistent data to perform a risk assessment, dietary exposures to germanium, lithium, strontium and tellurium were provided as supplementary data. The food groups highest contributors to exposure were "tubers and starches" for aluminium (27%), lead (39%) and copper (26%), "cereals and cereal products" for cadmium (54%) and manganese (35%), "fruits, vegetables and oilseeds" for barium (34%), molybdenum (49%) and nickel (31%), "beverages" for antimony (27%) and "fish" for vanadium (43% - lower bound). Measures should be recommended to maintain low levels of exposure before the problem could become an important health or trade issue.

Dietary exposure to trace elements and health risk assessment in the 2nd French Total Diet Study.

Dietary exposure of the French population to trace elements has been assessed in the second national Total Diet Study (TDS). Food samples (n = 1319) were collected between 2007 and 2009 to be representative of the whole diet of the population, prepared as consumed, and analyzed. Occurrence data were combined with national individual consumption data to estimate dietary exposure for adults and children mean and high consumers. Compared to the 1st French TDS performed in 2000-2004, exposure is higher for cadmium, aluminium, antimony, nickel, cobalt and lower for lead, mercury and arsenic. For aluminium, methylmercury, cadmium, lead and inorganic arsenic risk cannot be ruled out for certain consumer groups. It still appears necessary to continue undertaking efforts to reduce exposure to these elements. Due to the lack of robust toxicological data and/or speciation analysis in food on chromium, tin, silver and vanadium to perform a risk assessment, data on occurrence and dietary exposure are provided as Supplementary material. In order to minimize nutritional and chemical risks, the French Agency for Food, Environmental and Occupational Health & Safety (ANSES) reiterates its recommendation for a diversified diet (food items and origins).

Shellfish and residual chemical contaminants: hazards, monitoring, and health risk assessment along French coasts.

In this review, we address the identification of residual chemical hazards in shellfish collected from the marine environment or in marketed shellfish. Data, assembled on the concentration of contaminants detected, were compared with the appropriate regulatory and food safety standards. Moreover, data on human exposure and body burden levels were evaluated in the context of potential health risks.Shellfish farming is a common industry along European coasts. The primary types of shellfish consumed in France are oysters, mussels, king scallops, winkles,whelks, cockles, clams, and other scallops. Shellfish filter large volumes of water to extract their food and are excellent bioaccumulators. Metals and other pollutants that exist in the marine environment partition into particular organs, according to their individual chemical characteristics. In shellfish, accumulation often occurs in the digestive gland, which plays a role in assimilation, excretion, and detoxification of contaminants. The concentrations of chemical contaminants in bivalve mollusks are known to fluctuate with the seasons.European regulations limit the amount and type of contaminants that can appear in foodstuffs. Current European standards regulate the levels of micro-biological agents, phycotoxins, and some chemical contaminants in food. Since 2006, these regulations have been compiled into the "Hygiene Package." Bivalve mollusks must comply with maximum levels of certain contaminants as follows:lead (1.5 mg kg-1), cadmium (1 mg kg-1), mercury (0.5 mg kg-1), dioxins (4 pg g-1 and dioxins + DL-PCBs 8 pg g-1), and benzo[a]pyrene (10 µp.g kg-1).In this review, we identify the levels of major contaminants that exist in shellfish(collected from the marine environment and/or in marketed shellfish). The follow-ing contaminants are among those that are profiled: Cd, Pb, Hg, As, Ni, Cr, V,Mn, Cu, Zn, Co, Se, Mg, Mo, radionuclides, benzo[a]pyrene, PCBs, dioxins and furans, PAHs, TBT, HCB, dieldrin, DDT, lindane, triazines, PBDE, and chlorinated paraffins.In France, the results of contaminant monitoring have indicated that Cd, but not lead (< 0.26 mg kg-1) or mercury (< 0.003 mg kg-1), has had some non-compliances. Detections for PCBs and dioxins in shellfish were far below the regulatory thresholds in oysters (< 0.6 pg g-l), mussels (< 0.6 pg g-1), and king scallops (< 0.4 pg g-1). The benzo[a]pyrene concentration in marketed mussels and farmed shellfish does not exceed the regulatory threshold. Some monitoring data are available on shellfish flesh contamination for unregulated organic contaminants.Of about 100 existing organo stannic compounds, residues of the mono-, di-, and tributyltin (MBT, DBT, and TBT) and mono-, di-, and triphenyltin (MPT, DPT,and TPT) compounds are the most frequently detected in fishery products. Octyltins are not found in fishery products. Some bivalve mollusks show arsenic levels up to 15.8 mg kg-1. It seems that the levels of arsenic in the environment derive less from bioaccumulation, than from whether the arsenic is in an organic or an inorganic form. In regard to the other metals, levels of zinc and magnesium are higher in oysters than in mussels.To protect shellfish from chemical contamination, programs have been established to monitor water masses along coastal areas. The French monitoring network(ROCCH) focuses on environmental matrices that accumulate contaminants. These include both biota and sediment. Example contaminants were studied in a French coastal lagoon (Arcachon Bay) and in an estuary (Bay of Seine), and these were used to illustrate the usefulness of the monitoring programs. Twenty-one pesticidal and biocidal active substances were detected in the waters of Arcachon Bay during the summers from 1999 to 2003, at concentrations ranging from a few nanograms per liter to several hundred nanograms per liter. Most of the detected substances were herbicides, including some that are now banned. Organotin compounds have been detected in similarly semi-enclosed waters elsewhere (bays, estuaries, and harbors).However, the mean concentrations of cadmium, mercury, lead, and benzo[a]pyrene,in transplanted mussels, were below the regulatory limits.In 2007, the mean daily consumption of shellfish in the general French population was estimated to be 4.5 g in adults; however, a wide variation occurs by region and season (INCA 2 study). Tabulated as a proportion of the diet, shellfish consumption represents only 0.16% of overall solid food intake. However, the INCA 2 survey was not well suited to estimating shellfish consumption because of the small number of shellfish consumers sampled. In contrast, the mean consumption rate of bivalve mollusks among adult high consumers of fish and seafood products, i.e., adults who eat fish or seafood at least twice a week, was estimated to be 153 g week-1 (8 kg yr-1). The highest mean consumption is for king scallops (39 g week-1), followed by oysters (34 g week-1) and mussels (22 g week-1). Thus, for high seafood consumers, the contribution of shellfish to inorganic contaminant levels is 1-10% TWI or PTWI for Cd, MeHg, and Sn (up to 19% for Sn), and the arsenic body burden is higher for 22% of individuals studied.The human health risks associated with consuming chemical contaminants in shellfish are difficult to assess for several reasons: effects may only surface after long-term exposure (chronic risk), exposures may be discontinuous, and contamination may derive from multiple sources (food, air, occupational exposure, etc.).Therefore, it is not possible to attribute a high body burden specifically to shellfish consumption even if seafood is a major dietary contributor of any contaminant, e.g.,arsenic and mercury.The data assembled in this review provide the arguments for maintaining the chemical contaminant monitoring programs for shellfish. Moreover, the results presented herein suggest that monitoring programs should be extended to other chemicals that are suspected of presenting a risk to consumers, as illustrated by the high concentration reported for arsenic (in urine) of high consumers of seafood products from the CALIPSO study. In addition, the research conducted in shellfish-farming areas of Arcachon Bay highlights the need to monitor TBT and PAH contamination levels to ensure that these chemical pollutants do not migrate from the harbor to oyster farms.Finally, we have concluded that shellfish contamination from seawater offers a rather low risk to the general French population, because shellfish do not constitute a major contributor to dietary exposure of chemical contaminants. Notwithstanding,consumer vigilance is necessary among regular shellfish consumers, and especially for those residing in fishing communities, for pregnant and breast-feeding women,and for very young children.

Methylmercury exposure assessment using dietary and biomarker data among frequent seafood consumers in France CALIPSO study.

BACKGROUND: Seafood is considered by toxicologists as the main source of methylmercury (MeHg), but little data is available concerning contamination of seafood and MeHg status of French frequent consumers. OBJECTIVES: The objectives were to assess food exposure and biomarker of exposure of MeHg from a group of frequent consumers of seafood. METHODS: Two approaches to exposure assessment were used: the currently used food intake and the biomarker of exposure. A validated food frequency questionnaire (FFQ) was used to assess seafood consumptions for 80 products of 385 frequent consumers aged 18 and over in four French coastal areas. Seafood samples were collected in each region considering preservation methods and supply habits according to a total diet study sampling. Food samples were analyzed for MeHg. Exposure was assessed by combining consumptions with contamination data. Whole blood samples were collected from the volunteers and analyzed for MeHg. RESULTS: The mean dietary exposure to MeHg or weekly intake (WI FFQ) was 1.51+/-1.17 microg/kg bw/wk. Thirty-five percent of the subjects exceed the Joint Expert Committee on Food Additives (JECFA) provisional tolerable weekly intake (PTWI), whereas the use of the biological results with the JECFA/Environmental Protection Agency (EPA) one-compartment pharmacokinetic model to calculate weekly intake (WI PKM) shows that only 2% of subjects exceed the PTWI. The mean of the individual ratios WI FFQ/WI PKM is 4.3 and the higher the WI FFQ and the blood MeHg level, the lower is the ratio, close to 1-2. CONCLUSIONS: These analyses support the assumption that the calculated dose of methylmercury is overestimated with the FFQ-based method used in this study. Since FFQ are commonly used in risk assessments, the overestimate of dose is public health protective and this finding is somewhat reassuring from a public health point of view, especially since the JECFA or EPA have applied uncertainty factors of 3.2 or 3, respectively, to take into account the inter-individual pharmacokinetic variability.