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(Cr(VI)) - ASL di Brescia

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Chromium in drinking
water
Eugenia Dogliotti
Member of the CONTAM Panel, EFSA
Head of the Unit of Molecular Epidemiology,
Istituto Superiore di Sanità
ACKNOWLEDGEMENTS
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
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
2
INTRODUCTION - WHAT IS CHROMIUM
 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.
3
TERMS OF REFERENCE (TORs)
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
Cr(VI)
 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
4
Main title
LA VALUTAZIONE DEL RISCHIO
IDENTIFICAZIONE DEL PERICOLO
E.Testai, ISS
5
Main title
LA VALUTAZIONE DEL RISCHIO
IDENTIFICAZIONE DEL PERICOLO
E.Testai, ISS
6
Main title
LA VALUTAZIONE DEL RISCHIO
IDENTIFICAZIONE DEL PERICOLO
(minimum LB)
CARATTERIZZAZIONE DEL PERICOLO
(tossicocinetica, tossicità in modelli animali, studi epidemiologici)
E.Testai, ISS
7
Main title
LA VALUTAZIONE DEL RISCHIO
IDENTIFICAZIONE DEL PERICOLO
Relazione dose-effetto
Derivazione di
valori di
partenza
(PoD)
CARATTERIZZAZIONE
DEL RISCHIO
CARATTERIZZAZIONE DEL PERICOLO
(tossicocinetica, tossicità in modelli animali, studi epidemiologici)
E.Testai, ISS
8
Main title
Un po’ di nomenclatura…..






NO(A)EL
LO(A)L
BMDL
TDI
MRL
MOE
9
Main title
NO(A)EL - LO(A)EL
E.Testai, ISS
10
Main title
BMDL
E.Testai, ISS
11
Main title
EFFETTO CRITICO
TDI=MRL
E.Testai, ISS
12
Main title
MARGIN OF EXPOSURE (MOE)
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).
13
PREVIOUS RISK ASSESSMENTS
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).
14
RISK ASSESSMENT PARADIGM
HAZARD IDENTIFICATION
EXPOSURE ASSESSMENT
Levels in relevant food groups, food
consumption data, dietary exposure,
specific groups of the
population/species, time trends…
Occurrence data x Food/Feed consumption
HAZARD CHARACTERISATION
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
...
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.
15
Main title
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.
16
OCCURRENCE DATA
EFSA Call for data
• Results from 11 MSs (> 80% of the results from
Germany)
• Collected between 2000-2012
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).
17
OCCURRENCE DATA
Cr(VI)
 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.
18
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
19
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’).
20
HAZARD CHARACTERISATION
Toxicokinetics – Cr(III) and Cr(VI)




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.
21
Main title
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).
22
Main title
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.
ORAL UPTAKE
OF Cr(VI)
INTRACELLULAR
REDUCTION TO Cr(III)
Cr(III) DNA
ADDUCTS
MUTATIONS
ROS AND
OXIDATIVE
STRESS
DNA DAMAGE
MOA1
REDUCTION
TO Cr(III)
IN GI TRACT
EXCRETION OF
Cr(III)
ABSORPTION
AND CELLULAR
UPTAKE OF Cr(VI)
REDUCTION TO
Cr(V) REACTING
WITH H2O2
MOA2
23
Main title
MODE OF ACTION
24
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).
25
Main title
CARATTERIZZAZIONE DEL RISCHIO
VALUTAZIONE ESPOSIZIONE
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)
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
26
Main title
RISK CHARACTERISATION – CR(VI)
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 leftcensored data and should be interpreted considering the
uncertainties in the extrapolation from experimental animals to
humans.
27
Main title
RISK CHARACTERISATION – CR(VI)
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.
28
Main title
OVERALL CONCLUSIONS
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.
29
UNCERTAINTIES
 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
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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RECOMMENDATIONS

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.
31
THANK YOU FOR YOUR ATTENTION
QUESTIONS?
32
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