Chromium in drinking water

Eugenia Dogliotti Member of the CONTAM Panel, EFSA

Head of the Unit of Molecular Epidemiology, Istituto Superiore di Sanità

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The CONTAM Panel and the WG on chromium and nickel

Experts:

Alessandro Di Domenico, Eugenia Dogliotti (chair), Lutz Edler, Michael DiNovi, Antonio Mutti, Ivonne Rietjens, Guerin Thierry, Henk van Loveren and Christiane Vleminckx.

EFSA staff:

BIOCONTAM and DATA Units

ACKNOWLEDGEMENTS

European competent authorities

for providing occurrence data on chromium in food and drinking water, and supporting the consumption data collection for the Comprehensive European Food Consumption Database.

Slides kindly provided by Marco Binaglia BIOCONTAM Unit – Team CONTAM

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Beside its elemental state, Cr can exist in a variety of oxidation states. Trivalent and hexavalent (Cr(III) and Cr(VI)) are the more stable and largely predominant states

Cr can be present in food and drinking water both from natural anthropogenic sources. The natural presence is mainly related to Cr(III), whereas Cr(VI) is most commonly present as a result of industrial emissions in the environment.

Cr is widely distributed in the earth’s crust, mainly as Cr(III) (e.g. in ferrochromite (FeCr2O4 or FeOCr2O3))

Industrial applications of Cr include stainless steel production, electroplating, leather tanning, and manufacture of e.g. catalysts, pigments, paints, glass and ceramics.

INTRODUCTION - WHAT IS CHROMIUM

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The Hellenic Food Authority (EFET) asked EFSA for a scientific opinion on the risk to human health related to the presence of chromium (Cr) in food, addressing

particularly the presence of chromium in vegetables and hexavalent Cr (Cr(VI)) in bottled water

TERMS OF REFERENCE (TORs)

To consider any relevant information on toxicity of Cr(VI) for all the relevant toxicological endpoints

To assess the contribution to human exposure to total Cr of Cr(VI) in drinking water

To perform the exposure assessment taking into account recent

analytical results and the consumption patterns of specific (vulnerable) groups of the population

Cr(VI)

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LA VALUTAZIONE DEL RISCHIO

Main title

E.Testai, ISS

IDENTIFICAZIONE DEL PERICOLO

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LA VALUTAZIONE DEL RISCHIO

Main title

E.Testai, ISS

IDENTIFICAZIONE DEL PERICOLO

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LA VALUTAZIONE DEL RISCHIO

Main title

E.Testai, ISS

CARATTERIZZAZIONE DEL PERICOLO (tossicocinetica, tossicità in modelli animali, studi epidemiologici)

IDENTIFICAZIONE DEL PERICOLO

(minimum LB)

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LA VALUTAZIONE DEL RISCHIO

Main title

E.Testai, ISS

CARATTERIZZAZIONE DEL PERICOLO (tossicocinetica, tossicità in modelli animali, studi epidemiologici)

CARATTERIZZAZIONE DEL RISCHIO

Relazione dose-effetto

Derivazione di valori di partenza

(PoD)

IDENTIFICAZIONE DEL PERICOLO

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Un po’ di nomenclatura…..

NO(A)EL

LO(A)L

BMDL

TDI

MRL

MOE

Main title

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NO(A)EL - LO(A)EL

Main title

E.Testai, ISS

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BMDL

Main title

E.Testai, ISS

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EFFETTO CRITICO

Main title

E.Testai, ISS TDI=MRL

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MARGIN OF EXPOSURE (MOE)

Main title

Il MOE è uno strumento utilizzato per caratterizzare il rischio derivante dall’esposizione a sostanze genotossiche e cancerogene

che possono essere presenti nella filiera alimentare

MOE= DOSE A CUI AVVIENE L’EFFETTO AVVERSO (BMDL) LIVELLO DI ESPOSIZIONE

Il MOE fornisce un’indicazione del grado di preoccupazione per la sicurezza ma non quantifica il rischio. Un MOE pari o superiore a 10000, se si basa sul limite inferiore della dose di riferimento (BMDL) derivante da uno studio su animali, sarebbe a un basso rischio da un punto di vista di salute pubblica (EFSA, 2005).

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Cr(VI) IARC (International Agency for Research on Cancer) classified Cr(VI) compounds as carcinogenic to humans (Group I) with respect to the cancer of the lung, nose and nasal sinuses.

WHO established a guideline value for total Cr in water of 0.05 mg/litre (2003, provisional guideline value)

ATSDR (Agency for Toxic Substances and Disease Registry, 2012) established a minimum risk level for oral chronic exposure of 0.001 mg/kg b.w. per day for non neoplastic effects (diffuse epithelial hyperplasia of the duodenum in mice).

IPCS (International Programme on Chemical Safety, 2013) established an oral TDI of 0.9 µg /kg b.w. per day for non neoplastic effects (diffuse epithelial hyperplasia of the duodenum in mice).

PREVIOUS RISK ASSESSMENTS

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RISK CHARACTERIZATION Relate exposure to a chemical in a given population with toxicological effects

(health based guidance value/margin of exposure (MOE)) and concludes on the likelihood of adverse effects.

HAZARD IDENTIFICATION

EXPOSURE ASSESSMENT HAZARD CHARACTERISATION

Levels in relevant food groups, food consumption data, dietary exposure,

specific groups of the population/species, time trends…

Toxicokinetic variability (ADME), acute/sub/chronic toxicity, human data, genotox, mode/mechanism of action,

dose-response for critical effect, derivation of a health based guidance value

... Occurrence data x Food/Feed consumption

RISK ASSESSMENT PARADIGM

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HOW CHROMIUM IS MEASURED - METHODS

Several analytical methods are available for the determination of total Cr in food and water, generally based on atomic absorption spectrometry and increasingly on inductively coupled plasma mass spectrometry (ICP-MS).

Liquid chromatography (LC) coupled to inductively coupled plasma mass spectrometry (ICP-MS), and the use of speciated isotope dilution (SID) are a suitable tool for speciation of chromium in both food and water.

Standardised methods for the determination of total chromium in food and water are available.

For Cr(VI) analysis, two standardised methods exist for various types of water.

Main title

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81247 analytical results available 33% of the results were in food, 65% in drinking water (52735) > 99% of the results were reported as (unspecified) Cr or total Cr Only 88 results on Cr(VI) were reported, all for bottled water samples.

In the final dataset, 50% of the results in food and 91% of the results in drinking water were left-censored.

For the 88 samples of bottled water, 11% reported no quantified levels both for total Cr and Cr(VI).

OCCURRENCE DATA

EFSA Call for data • Results from 11 MSs (> 80% of the results from

Germany)

• Collected between 2000-2012

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OCCURRENCE DATA

Among the data on water, tap water samples were the most reported (60.6 %) with mean Cr occurrence values of 0.2 µg/L and 1.9 µg/L at the LB and the UB, respectively.

In bottled water, the mean occurrence values were similar, ranging between 0.3 µg/L for carbonated mineral water (LB) and 3.4 µg/L at the UB reported for unspecified bottled water.

The 71 samples of bottled water quantified for Cr(VI) and total Cr showed a ratio Cr(VI)/total Cr of 0.97.

Cr(VI)

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EXPOSURE ASSESSMENT

Approach for exposure assessment in drinking water

The CONTAM Panel decided to consider all the chromium present in drinking water as Cr(VI). This assumption was based on the evidence that those water samples where both Cr(VI) and total Cr were quantified had an average ratio Cr(VI)/total Cr of 0.97. In addition the water intended for human consumption is usually treated with oxidizing agents to make it potable, which could favour the presence of Cr(VI) over that of Cr(III).

EFSA comprehensive european food consumption data base BANCA DATI PARTICOLAREGGIATA DELL’EFSA SUI CONSUMI ALIMENTARI IN EU

•rapida selezione tra esposizione cronica ed esposizione acuta •indagini sulle abitudini alimentari e i dati sui consumi di alimenti per ciascun Paese sono suddivisi per categoria (es. età, gruppo di alimenti (quasi 160) e tipo di consumo) •calcoli su misura per ciascuna categoria di consumatori

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Main title

EXPOSURE ASSESSMENT - CR(VI) IN DRINKING WATER DRINKING WATER

The mean chronic exposure to Cr(VI) ranged from 0.7 (minimum LB) to 159.1 ng/kg b.w. per day (maximum UB).

The 95th percentile exposure to Cr(VI) ranged from 2.8 (minimum LB) to 320.2 ng/kg b.w. per day (maximum UB).

ONLY BOTTLED WATER

The mean chronic exposure to Cr(VI) ranged from < 0.1 (minimum LB) to 149.8 ng/kg b.w. per day (maximum UB, infants).

The 95th percentile exposure to Cr(VI) ranged from 0.0 (minimum LB) to 148.7 ng/kg b.w. per day (maximum UB, ‘Toddlers’).

The highest exposure levels to Cr(VI) through the consumption of drinking water and bottled water were estimated in the youngest populations (‘Infants’ and ‘Toddlers’).

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Overall Cr(III) has low bioavailability, although a slightly higher bioavailability is observed for organic Cr(III)-complexes.

Conversely, Cr(VI) is able to cross cellular membrane.

Following ingestion, the absorption and tissue distribution of Cr(VI) depend strongly on the rate and extent of its reduction in the gastrointestinal tract but also on the ligands bound to Cr(VI) or the Cr(III) formed upon reduction of Cr(VI).

The data available so far support that reduction along the gastrointestinal tract is efficient but that it cannot be excluded that even at low dose levels a small percentage of Cr(VI) escapes gastrointestinal reduction to Cr(III) and is systemically absorbed.

HAZARD CHARACTERISATION

Toxicokinetics – Cr(III) and Cr(VI)

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HAZARD CHARACTERISATION Toxicity – Cr(VI)

Human data not suitable to assess toxicity.

Following repeated exposure to Cr(VI) in rodents, the major target organs were the gastrointestinal tract, liver, kidney and haematological system.

The relevant NOAEL for non-neoplastic changes in chronic toxicity studies was 0.21 mg/kg b.w. per day in rats. No NOAEL could be identified in mice (LOAEL of 0.38 mg/kg b.w. per day).

Effects on reproduction and development were observed at doses higher than those causing effects in the identified target organs.

Cr(VI) compounds are genotoxic in vitro and in vivo (in particular following intraperitoneal injection).

Cr(VI) is carcinogenic following ingestion in rats (tumours of the squamous epithelium of the oral cavity) and mice (tumours of the epithelial tissue of the small intestine).

Main title

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HAZARD CHARACTERISATION MODE OF ACTION – Cr(VI)

Intracellular reduction of Cr(VI) generates lower Cr valences, facilitating the production of ROS, and ultimately Cr(III), which generates DNA adducts, representing the two possible modes of action for induction of carcinogenicity.

Main title

ORAL UPTAKE OF Cr(VI)

REDUCTION TO Cr(III)

IN GI TRACT

EXCRETION OF Cr(III)

ABSORPTION AND CELLULAR

UPTAKE OF Cr(VI)

INTRACELLULAR REDUCTION TO Cr(III)

REDUCTION TO Cr(V) REACTING

WITH H2O2

ROS AND OXIDATIVE

STRESS

DNA DAMAGE

MUTATIONS Cr(III) DNA ADDUCTS

MOA1

MOA2

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MODE OF ACTION

Main title

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HAZARD CHARACTERISATION

Dose response analysis and Margin of Exposure (MOE) – Cr(VI)

The CONTAM Panel applied a Margin of Exposure (MOE) approach for the risk assessment of Cr(VI).

Benchmark dose (BMD) modelling was used to calculate the RPs for neoplastic and non-neoplastic effects of Cr(VI).

Neoplastic effects

BMDL10 of 1.0 mg/kg b.w. per day was calculated as RP for the combined incidence of adenoma or carcinoma in the mouse small intestine.

Non-neoplastic effects

BMDL10 of 0.11 mg/kg b.w. per day calculated as RP for non-neoplastic lesions (increased incidence of diffuse epithelial hyperplasia in the male mouse duodenum).

BMDL05 of 0.2 mg/kg b.w. per day calculated as RP for haematological effects (decreased haematocrit in male rats).

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CARATTERIZZAZIONE DEL RISCHIO

Main title

ESPOSIZIONE MEDIA CRONICA 0.7-159.1 ng/kg b.w. per day (min LB-max UB) ESPOSIZIONE DEL 95° PERCENTILE 2.8-320.2 ng/kg b.w. per day (min LB-max UB)

VALUTAZIONE ESPOSIZIONE VALORI DI RIFERIMENTO

EFFETTI NEOPLASTICI BMDL10 = 1.0 mg/kg b.w. per day EFFETTI NON NEOPLASTICI BMDL10 = 0.11 mg/kg b.w. per day EFFETTI EMATOTOSSICI BMDL05 = 0.2 mg/kg b.w. per day

MOE (margin of exposure) EFFETTI NEOPLASTICI >= 10.000

EFFETTI NON NEOPLASTICI/EMATOTOSSCI>= 100 BASSO RISCHIO

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RISK CHARACTERISATION – CR(VI)

Main title

Neoplastic effects

Genotoxic carcinogen. MOE of 10 000 or higher considered of low concern from a public health point of view.

MOEs calculated for mean exposure via consumption of drinking were all above 10000 in all the age groups with the exception of infants (MOE range 6300-71000 at max UB-min LB).

MOEs below 10000 were calculated for 95th percentile exposure for Infants (3100-21000 at max UB-min LB), Toddlers (4200-62000) and Other children (6600-360000)

Similar results were obtained considering consumption of only bottled water

The MOE results were influenced by the high proportion of left- censored data and should be interpreted considering the uncertainties in the extrapolation from experimental animals to humans.

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RISK CHARACTERISATION – CR(VI)

Main title

Non-neoplastic effects

The lowest MOEs for non-neoplastic lesions across all dietary surveys and age groups were 690 and 340 for mean and 95th percentile exposure levels (max UB), respectively.

The lowest MOEs for haematological effects across all dietary surveys and age groups were 1300 and 630 for mean and 95th percentile exposure levels (max UB), respectively.

CONTAM Panel considered that for the critical thresholded effects, MOEs larger than 100 would indicate a low concern for human health.

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OVERALL CONCLUSIONS

Main title

EFFETTI NEOPLASTICI Gli attuali livelli di esposizione al Cr(VI) attraverso il consumo di tutti I tipi di acqua costituiscono un BASSO RISCHIO per i consumatori medi. Ci può essere un RISCHIO POTENZIALE per i forti consumatori particolarmente nella fascia di età più giovane For neoplastic effects, the current levels of exposure to Cr(VI) via the consumption of all types of drinking water or of bottled water only are of low concern for the average consumers. There might be a potential concern for high consumers particularly in the younger age groups.

EFFETTI NONNEOPLASTICI/EMATOTOSSICI Gli attuali livelli di esposizione al Cr(VI) attraverso il consumo di tutti I tipi di acqua NON costituiscono un RISCHIO per la salute pubblica For non-neoplastic lesions and haematological effects the current exposure levels to Cr(VI) via drinking water are of no concern from a public health point of view.

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Uncertainty on analytical results (mainly from one MS)

Cr(VI) Very limited data on speciation in water No data on Cr(VI) in food Insufficient data on the impact of exposure from smoking to dietary exposure Uncertainty in the level of reduction of Cr(VI) in the human gastrointestinal

tract as compared to rodents Uncertainty in the efficiency of reduction at doses relevant to human exposure

as compared to higher doses used in bioassays

UNCERTAINTIES

The CONTAM Panel concluded that the impact of the uncertainties on the risk assessment of exposure to Cr(VI) in

drinking water is very large

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Data should be generated using sensitive analytical methodologies which specifically measure the content of Cr(III) and Cr(VI) in food and drinking water in different EU Member States.

Further data are needed to characterise the percentage of Cr(VI) reduction in the GI tract at doses relevant for human exposure and at the doses used in the rodent bioassays.

RECOMMENDATIONS

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THANK YOU FOR YOUR ATTENTION

QUESTIONS?