Regulatory Toxicology and Pharmacology 130 (2022) 105122

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Regulatory Toxicology and Pharmacology

journal homepage: www.elsevier.com/locate/yrtph

Review of regulatory reference values and background levels for heavy

metals in the human diet
Candace Wong a, Stephen M. Roberts b, *, Imad Neal Saab c
a
University of Rochester, Department of Environmental Medicine, Toxicology Program, 601 Elmwood Ave., Box 850, Rochester, NY, 14642, USA
b
University of Florida, Center for Environmental and Human Toxicology, 2187 Mowry Road, Gainesville, FL, 32611, USA
c
Institute for Advancement of Food and Nutrition Sciences (IAFNS), 740 15th St. NW, Ste 600, Washington, DC, 20005, USA

A R T I C L E I N F O A B S T R A C T

Handling Editor: Dr. Lesa Aylward The U.S. Food and Drug Administration (US FDA) has identified dietary exposure to heavy metals as a public
health concern, focusing particularly on arsenic, cadmium, lead, and mercury. One way to determine current risk
Keywords: is to compare established safe exposure limits (reference values) with current population-based dietary back­
Cadmium ground levels. Information on reference values and dietary background exposures for these metals and chromium
Arsenic
were critically evaluated in support of an interactive risk assessment screening tool (Heavy Meals Screening Tool
Mercury
[HMST]). Cadmium, arsenic, and mercury background exposures from food and water were found to be below
Lead
Chromium current safe US regulatory limits based on non-cancer effects, while lead background exposures were nearly
Dietary exposure equivalent to the US FDA’s newest interim reference level for children. Because detections of chromium in foods
are infrequent and data on speciation (trivalent versus hexavalent) are limited, chromium was excluded from the
HMST. The focus of this work was to present U.S. based reference and background exposure values, although the
tool can use inputs that may be more appropriate for other countries, cultures, and situations. With emerging
science, new health endpoints, and changes in food consumption trends, both reference values and background
exposure levels are likely to evolve.

1. Introduction
Exposures to heavy metals through dietary intake have been iden­
tified as a public health concern by the U.S. Food and Drug Adminis­
tration (FDA). The goal of the newly formed Toxic Elements Working
group within the FDA is to reduce exposure of heavy metals in food,
dietary supplements, and cosmetics. The Toxic Elements Working Group
has prioritized heavy metals such as lead, mercury, arsenic, and cad­
mium as high levels of exposure to these metals are likely to have the
largest impact on public health. Regulations such as the Federal Food,
Drug, and Cosmetic Act and Clean Water Act monitor and set quality
standards for food and water consumption (EPA, 2019c; Schultz and
Schultz, 2012). However, due to continuing concern regarding heavy
metals in foods for babies and young children, the FDA has also intro­
duced its “Closer to Zero” action plan to reduce exposure of these metals
in this vulnerable population (FDA 2021).
The potential presence of heavy metals of concern (arsenic, lead,
mercury, cadmium) in food products and ingredients is a concern
because these metals are ubiquitous in the environment and, as such,
can reach the food supply via accumulation in plants, animals, and water
sources (Jaishankar et al., 2014). Ingestion of heavy metals can
contribute to a wide variety of adverse health effects, including organ
damage, developmental alterations, and cancer (ATSDR, 2007, 2012b;
Bellinger, 2008; Faroon et al., 2017; FDA, 2014).
In 2015, the International Life Sciences Institute North America (now
the Institute for Advancement of Food and Nutrition Sciences [IAFNS])
developed the Metal Dietary Exposure Screening Tool (MDEST; Tran
et al., 2015; https://iafns.org/our-work/research-tools-open-data/meta
l-dietary-exposure-screening-tool/) to facilitate the rapid assessment of
risks from heavy metals in food and food ingredients. This Excel-based
tool provided information on potential risks from heavy metals in food
products by comparing estimated exposure to safe exposure limits taking
into consideration background dietary intake. Safe oral exposure limits,
or reference values, were selected from values available from various
agencies (e.g., Environmental Protection Agency (EPA) reference doses
and Joint FAO/WHO Expert Committee on Food Additives (JECFA)
provisional tolerable intake values). Background dietary intakes of the
heavy metals were estimated using information from both consumption

* Corresponding author. Center for Environmental & Human Toxicology, University of Florida, Box 110885, Gainesville, FL 32611, USA.
E-mail addresses: candacewong888@gmail.com (C. Wong), smroberts@ufl.edu (S.M. Roberts), nsaab@iafns.org (I.N. Saab).

https://doi.org/10.1016/j.yrtph.2022.105122
Received 1 October 2021; Received in revised form 2 January 2022; Accepted 12 January 2022
Available online 26 January 2022
0273-2300/© 2022 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
C. Wong et al. Regulatory Toxicology and Pharmacology 130 (2022) 105122

databases and residue studies. Although the tool was not stated as pri­ from multiple agencies were identified through June 2019 for non-
marily intended for use in the U.S., strong preference was given to cancer-based endpoints (Table 1).
exposure data taken from U.S. populations. Data on food consumption
were derived from the U.S. Department of Agriculture (USDA) and the
U.S. Department of Health and Human Services (DHHS) two-day food 2.2. Background dietary intake
interview called “What We Eat in America” (WWEIA) as part of the
yearly National Health and Nutrition Examination Survey (NHANES) Both food and water intake were taken into consideration to derive
(USDA, 2016). These data were then compiled into a food commodity the total background exposure level. For determining total background
database to better understand amount of consumption and shifting exposure level for each metal, a literature search was completed for food
trends. Residue studies, such as the Total Diet Study (TDS) conducted by and water intake. The search for heavy metal exposure from food con­
the FDA, determine the level of various residues (including heavy sumption was focused on studies that utilized a combination of chemical
metals) in different food types across the United States (FDA, 2019). By residue and consumption data via PubMed. As the scope of this work is
combining the amount of food consumed by users (consumption data­ U.S. centric, studies were limited to use of U.S. derived resources.
bases) and the concentration of a given contaminant found in different Studies that used chemical residue studies from the Total Diet Study
food types (residue studies), estimates of the dietary background conducted by the FDA were given higher preference due to its well-
consumed by Americans on a day-to-day basis were obtained and used in established and consistent sampling over decades as well as its use by
the model. the FDA Toxic Elements Working Group. The Total Diet Study monitors
The MDEST was recently replaced with the Heavy Metals Screening about 800 different chemicals and contaminants in food ingredients and
Tool (HMST; http://metaltool.test.jifsan.org/), an interactive, web- prepared foods across the United States four times a year (FDA, 2018b).
based platform developed in partnership between the Institute for Studies using U.S. based consumption data from NHANES What We Eat
Advancement of Food and Nutrition science (IAFNS) and the Joint in America were also given higher preference. This yearly report in­
Institute for Food Safety and Applied Nutrition (JIFSAN). In this updated cludes 2-day dietary intake information for Americans (CDC, 2015).
version of the tool, reference values and background dietary exposures Studies that included only analytical metal quantitation in biological
for arsenic, cadmium, lead, mercury, and chromium incorporated into samples, such as quantitative metal blood analysis, were not considered
the model as defaults were re-evaluated and updated resulting in several in the literature search because of variability in estimating the equiva­
changes. lent food intake value.
In the HMST tool, users first choose a heavy metal and food item. For determining exposures of heavy metals from water consumption,
Expected daily intake (μg/kg/day; mean, 90th, 95th, and 99th percen­ values were selected from water exposure data or conservatively based
tile) of that metal is calculated based on food consumption and chemical on water exposure limits, such as the EPA’s Maximum Contaminant
residue information from NHANES (1999–2016) and TDS (2003–2014) Levels (MCL) for drinking water. Background exposure levels (converted
data. These database values were updated from the past version of the to μg/kg/day if necessary) corresponded with appropriate age-matched
tool. To contextualize the estimated daily intake of the metal (μg/kg/ values.
day), this value is compared to both safe reference values and back­
ground exposure levels for that given metal. The focus of this manuscript 3. Arsenic
is to describe how updated default safe reference values and background
exposure levels for arsenic, cadmium, lead, mercury, and chromium 3.1. Arsenic reference value
were chosen, with the understanding that the reference and background
exposure levels can be customized by the user for regional or population The EPA developed an oral reference dose of 0.3 μg/kg/day for
specific calculations. inorganic arsenic in 1991 (EPA, 1995). This value was derived from
The results of this re-evaluation are presented here, and the ratio­ studies on rural inhabitants in Taiwan suffering from arsenism due to
nales for incorporation of specific values and data into the new model chronic exposures of arsenic in well water (Tseng, 1977; Tseng et al.,
are explained. As with the original model, default inputs were primarily
from U.S. sources. However, other values can be substituted in the model Table 1
if needed to make the outputs more useful in other countries or specific List of current heavy metal reference values.
situations where the defaults are not appropriate. Metals/ Reference Value Agency and Year
Metalloids
2. Information sources for dietary exposure and exposure limits Inorganic 2.14 μg/kg/day JECFA 1988 EPA 1991 ATSDR
Arsenic 0.3 μg/kg/day 2007
2.1. Reference values 0.3 μg/kg/day
Cadmium 1 μg/kg/day EPA 1989 JECFA 2010 EFSA 2011
0.83 μg/kg/day ATSDR 2012
Daily maximum safe exposure levels for heavy metals were identified
0.36 μg/kg/day
from values available from agencies such as the EPA, Agency for Toxic 0.1 μg/kg/day
Substances and Disease Registry (ATSDR), and JECFA. The names given Lead Young Children: 0.26 μg/ FDA 2018
to these exposure limits often vary by agency, using terms such as “Oral kg/day*
Reference Dose”, “Provisional Total Daily Intake”, or “Minimal Risk Older Children and
Adults:
Level”. Although the method for their derivation can also vary, their 0.16 μg/kg/day**
purpose is the same. To avoid confusion, these values are collectively Methylmercury 0.3 μg/kg/day ATSDR, 1999
termed “reference values” in this manuscript. All reference values 0.1 μg/kg/day EPA (2001)
considered for the model are derived from dose-response data 0.23 μg/kg/day JECFA 2007
0.19 μg/kg/day EFSA 2012
comparing exposures with observed effects in humans or laboratory
Chromium (III) 1500 μg/kg/day EPA (1999)
animals. Exposure limits based on other considerations such as cost of 300 μg/kg/day EFSA (2014)
compliance or technical feasibility of implementation were not consid­ Chromium (VI) 3 μg/kg/day EPA (1998)
ered. Reference values used in the model were all based on prevention of 0.9 μg/kg/day ATSDR 2012
non-cancer health effects. Omission of exposure limits based on poten­ 2.2 μg/kg/day Health Canada (2018)

tial carcinogenicity is a significant limitation of the model for some *Assuming a 11.4 kg 1 year old.
metals, as discussed in a subsequent section. Current reference values **Assuming an 80 kg adult.

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C. Wong et al. Regulatory Toxicology and Pharmacology 130 (2022) 105122

1968) (Table 2). In 2007, the ATSDR derived a Minimal Risk Level Table 3
(MRL) value of 0.3 μg/kg/day based upon the same pivotal study, point Total background levels of heavy metals.
of departure (POD), and uncertainty factor (ATSDR, 2007). JECFA Metal/ Food Intake Food Intake Water Total Dietary
determined a much higher value with a Provisional Tolerable Weekly Metalloid Study Background Intake Background
Intake (PTWI) of 0.015 mg/kg/week (2.14 μg/kg/day) in 1988 (JECFA, Level Level* Level
1988). However, after further analysis in 2011, this value was with­ Inorganic Xue et al., 2010 0.02 μg/kg/ 0.16 μg/ 0.18 μg/kg/
drawn as being insufficiently protective (JECFA, 2011a) and has not Arsenic day kg/day day
been replaced. Cadmium JECFA (2013) 0.18 μg/kg/ 0.08 μg/ 0.26 μg/kg/
day kg/day day
For the update, a reference value of 0.3 μg/kg/day is retained, citing Lead Spungen (2019) 0.11 μg/kg/ 0.13 μg/ 0.24 μg/kg/
the EPA reference dose as the source (Table 4). The durability of this (children 1–3 day Children kg/day day
value is evident in that the ATSDR reached the same value 16 years later, yrs) Children
even considering newer studies published after the EPA reference dose ^,#
JECFA 2011 0.03 μg/kg/ 0.075 μg/ 0.11 μg/kg/
was derived. We note that the EPA started a reassessment of inorganic
(Adult) day kg/day day
arsenic in 2003 as part of the Integrated Risk Information System (IRIS) Adult Adults
program (EPA, 2019a), but as of the publication of this report, this ^,##
reassessment has remained in the initial stages. Methylmercury Xue et al., 2012 0.02 μg/kg/ 0.03 μg/ 0.05 μg/kg/
day kg/day day
Total Moschandreas 0.47 μg/kg/ 1.5 μg/ 1.97 μg/kg/
3.2. Arsenic food intake background exposure levels Chromium et al., 2002 day kg/day day
*
Water intake levels based on current EPA Maximum Contaminant Levels
In 2015, Tran et al. determined that the total background exposure unless noted.
levels for inorganic arsenic exceeded the reference values, so total ^
Median lead levels across 15 major U.S. cities derived from recent municipal
background exposure levels in the MDEST tool were estimated to be water quality reports.
95% of the reference value (Tran et al., 2015) (Table 5). For the update, #
Assuming an 11.4 kg 1-year old consuming 0.3 L of water.
information on arsenic exposure from food and drinking water was ##
Assuming an 80 kg adult consuming 1.2 L of water.
re-evaluated. Several studies have examined arsenic background level
exposures. Yost et al. (2004) determined background exposure levels for water sources (EPA, 2000a,b)]. They found that the background expo­
children using the USDA Continuing Survey of Food Intakes by In­ sure level was 3.5 μg/day for children ages 1–6 years old and 5.6 μg/day
dividuals (CSFII) (1994–1996) and the 1998 Supplemental Children’s for adults. Assuming an 11.4 kg 1-year old child and an 80 kg adult, the
Survey for consumption data. The consumption items from these two combined food and water arsenic background exposure level was 0.3
databases were matched with inorganic arsenic concentrations in foods μg/kg/day and 0.07 μg/kg/day, respectively. In 2010, Xue et al. (2010)
determined by Schoof and others (Schoof et al., 1999). Using these da­ determined arsenic background exposure levels for both children and
tabases, Yost et al. (2004) determined a background exposure level of adults using the FDA TDS from 1991 to 2004 and NHANES WWEIA data
3.2 μg/day for children 1–6 years old. The exposure background level from 2003 to 2004. Because the FDA TDS only measures total arsenic
would be 0.28 μg/kg/day, assuming an 11.4 kg 1-year old (EPA, 2011). concentrations, ratios based on Schoof et al., (1999) data were applied to
Three years later, a study by Tsuji et al. (2007) utilized the same con­ the TDS data to convert the total arsenic to inorganic arsenic concen­
sumption and residue studies as Yost et al. (2004), but also considered trations. They found that children 3–5 years old had arsenic background
contribution of arsenic from drinking water [surface water and ground

Table 2
Pivotal studies1 used to derive heavy metal reference values.
Metal/ Reference Value Pivotal Study Endpoint POD Value Uncertainty Factor
Metalloid

Inorganic 0.3 μg/kg/day (EPA Contaminated well water Skin lesions, hyperkeratosis NOAEL = 0.0008 mg/kg/ 3 – uncertainty in NOAEL for sensitive
Arsenic2 1991) (Tseng et al., 1968; and hyperpigmentation day individuals
Tseng 1977)
Cadmium 1 μg/kg/day (EPA US EPA 1985 Drinking Proteinuria NOAEL = 0.01 mg/kg/day 10
1989) Water Criteria Document
on Cadmium
Lead 0.26 μg/kg/day CDC Blood Lead 97.5th percentile of blood Calculated intake based on 10
Young Children Reference Values lead level distribution in blood lead level distribution
0.16 μg/kg/day children
Older Children and
Adults (FDA 2018)
Methylmercury 0.1 μg/kg/day (EPA Mother-infant pairs in Neurophysical effects in 1.3 μg/kg/day daily ingested Composite of 10 – uncertainty in cord
2001) Faroe Islands (Grandjean offspring at 7 years old maternal value to reach cord blood estimates and pharmacodynamic
et al., 1997) blood Hg concentration variability and uncertainty
Chromium (III) 1500 μg/kg/day ( Rats fed Cr2O3 bread ( Histological changes NOAEL = 1,468 mg/kg/day Composite 1000 – interspecies/
EPA 1999) Ivankkovic & Preussman interhuman variability, database
1975) deficiencies
Chromium (VI) 3 μg/kg/day (EPA Rats ingesting K2CrO4 Pathologic changes in tissue NOAEL = 2.5 mg/kg/day Composite 900 – interspecies/interhuman
1998) water (MACKENZIE variability, less than lifetime exposure
et al., 1958) duration, concerns based on human
studies
1
Pivotal studies include studies that are critical to the calculation of a final regulatory standard or level, or to the quantified costs, benefits, risks, and other impacts
on which a final regulation is based.
2
In 2003, EPA IRIS started a reassessment of inorganic arsenic (US EPA National Center for Environmental Assessment, 2019). As of May 2019, EPA released the
“Updated Problem Formulation and Systematic Review Protocol for the Inorganic Arsenic IRIS Assessment” in order to get feedback from the National Academy of
Sciences, EPA, other federal agencies, and the public to focus the objectives for the reassessment. This is a part of Step 1 in the EPA IRIS reassessment process (7 steps
total) (EPA IRIS, 2019).

3
C. Wong et al. Regulatory Toxicology and Pharmacology 130 (2022) 105122

Table 4 Level (MCL) of 0.01 mg/L (EPA, 2019b). This is the same level set by the
Comparison of dietary heavy metal reference values. FDA for bottled water, as well as by the WHO (FDA, 2019; WHO, 2011a).
Heavy Metal/ Current Reference Tran et al., 2015 Reference Assuming an 80 kg adult drinking 1.2 L of water per day (EPA, 2011), a
Metalloid Value2 Value daily intake of arsenic from water would be 0.16 μg/kg/day. It should be
Inorganic Arsenic 0.3 μg/kg/day 0.3 μg/kg/day noted that actual occurrence of arsenic in drinking water can be
Cadmium 1 μg/kg/day 0.83 μg/kg/day significantly lower or higher than this limit depending on the local water
Lead 0.26 μg/kg/day 6 μg/day (0-6y) source. For example, ground water sources can exceed the EPA MCL of
Children (11.4 kg 1 yr 15 μg/day (7y+) 0.01 mg/L, where more than 2.1 million Americans have been poten­
old)
0.16 μg/kg/day 25 μg/day (pregnant/
tially exposed in over 25 states (Ayotte et al., 2017; DeSimone et al.,
Adult (80 kg) lactating) 2014). However, comparisons of studies that measure total background
75 μg/day (adults) intake (food and water) with studies that measure food intake alone
Mercury 0.1 μg/kg/day (MeHg) 0.57 μg/kg/day (inorganic suggest water contributes very little to total inorganic arsenic intake.
Hg)
Tsuji et al., (2007) and Yost et al., (2004) derived nearly identical
Chromium (III) 1500 μg/kg/day 250 μg/day
Chromium (VI) 3 μg/kg/day 0.9 μg/kg/day background exposure-levels (0.3 vs 0.28 μg/kg/day for children 1–6
2
years old, respectively) using the same consumption and residue data­
Reported in this work.
bases. While Yost et al., 2004 only accounted for food intake, Tsuji et al.,
(2007) study measured both food and drinking water (ground and sur­
Table 5
face water) intake. This comparison suggests that for most individuals,
Comparing heavy metal total background levels. drinking water is not a significant source of inorganic arsenic intake.

Heavy Metal/ Current Tran et al., 2015 Background Value

Metalloid Background 3.3. Comparison of arsenic exposure with its reference value
Value3

Inorganic 0.18 μg/kg/day 0.285 μg/kg/day

Comparing the total U.S. background value of 0.18 μg/kg/day to the
Arsenic Default: 95% combined food + water (5% EPA derived reference value of 0.3 μg/kg/day demonstrates a two-fold
for tool use) margin of safety. Considering the identical pivotal study used across
Cadmium 0.26 μg/kg/day 0.36 μg/kg/day multiple international agencies, this reference value is not likely to be
Lead 0.24 μg/kg/day Total background assumed 50% of PTTI for
affected due to regional differences. However, background levels of
Children vulnerable population; 1/3 of PTDI for
adults arsenic may differ between regional groups due to cultural eating habits
0.11 μg/kg/day Total background assumed 50% of PTTI for (increased daily consumption of sources of arsenic such as rice and
Adults vulnerable population; 1/3 of PTDI for seaweed) and use of local ground water sources that may have higher
adults levels of arsenic than EPA regulated levels which can decrease the
Mercury 0.05 μg/kg/day 0.127 μg/kg/day
margin of safety.
Chromium (VI) 1.97 μg/kg/day 1.7 μg/kg/day
Water contribution only, no food
3
4. Cadmium (Cd)
Reported in this work.

4.1. Cadmium reference values

exposure levels at 0.05 μg/kg/day and adults at 0.02 μg/kg/day. Jara
and Winter used USDA CSFII from 1994 to 1996 with FDA TDS studies
from 2006 to 2008 to calculate arsenic background exposure levels (Jara
and Winter 2014). In order to convert the total arsenic from the TDS
database to inorganic arsenic, Jara and Winter assumed 9 different
consumption scenarios with varying proportions of marine versus
terrestrial contributions of inorganic arsenic. Based on these scenarios,
the range of arsenic exposure-background levels were 0.11–0.28
μg/kg/day for 2-year-old children and 0.02–0.08 μg/kg/day for adults.
The study of Jara and Winter (2014) is the most recent publication of
the studies reviewed, but the USDA CSFII database from 1994 to 1996
used in the study is dated. The nine different exposure scenarios used by
Jara and Winter to convert total arsenic concentrations in foods to
inorganic arsenic are based primarily on hypothetical situations and not
quantitative analysis. Other studies, such as Yost et al., (2004) and Tsuji
et al., (2007), utilized arsenic food concentrations published by Schoof
et al., (1999), which quantitatively measured both total and inorganic
arsenic. However, like Jara and Winter (2014), consumption data used
by Yost et al., (2004) and Tsuji et al., (2007) were derived from the
USDA CSFII database from 1994 to 1996. The study by Xue et al., (2010)
utilized relatively current databases for both the consumption and res­
idue databases (TDS, 1991–2004 and NHANES WWEIA from 2003 to
2004). Conversion rates from total to inorganic arsenic were also based
on quantitative data from Schoof et al., (1999). Because it is derived
from more recent databases along with quantitative measures to convert
to inorganic arsenic, the Xue et al., (2010) background exposures level
for arsenic in food for adults (0.02 μg/kg/day) was used for the updated
tool.
A background arsenic consumption from drinking water was
conservatively selected based upon the EPA Maximum Contaminant
JECFA determined a PTWI for cadmium of 0.007 mg/kg/day in 1988
and revised their PTMI to 25 μg/kg/month in 2010 (JECFA, 2010).
Converting this to a daily value, assuming 30 days in a month, the
Provisional Tolerable Daily Intake (PTDI) is 0.83 μg/kg/day. Reference
values from the EPA, EFSA, and ATSDR were also considered (Table 1).
Among these, the oldest is an oral reference dose of 1.0 μg/kg/day set by
the EPA in 1989. It was based on a No Observed Adverse Effect Level
(NOAEL) value of 200 μg Cd/g wet human renal cortex that did not
cause significant proteinuria (EPA, 1986). This was supported by a
primary study in Belgium (Buchet et al., 1990) and supported by similar
values from Japan (Nogawa et al., 1989). Using toxicokinetic modeling,
with an assumption of 2.5% absorption from food and 0.01% elimina­
tion from the body, this equated to a daily intake of 0.01 mg Cd/kg/day,
to which an uncertainty factor of 10 was applied to derive the reference
dose (EPA, 1989). A decade later, a draft assessment using a different
critical study and toxicokinetic modeling proposed a somewhat lower
reference dose of 0.7 μg/kg/day for protection of kidneys (EPA, 1999),
but was never adopted.
Also, in 2009, the ATSDR derived a chronic oral minimum risk level
(MRL) of 0.1 μg/kg/day (ATSDR, 2008). The basis for this MRL was
described in a toxicological profile released for public comment in
September 2008, with the final revision released in September 2012
(ATSDR, 2012b). Thirty-five epidemiological studies were reviewed, but
the pivotal studies used to derive the chronic oral MRL were epidemi­
ological studies in Europe (Sweden, Belgium) (Buchet et al., 1990; Järup
et al., 2000; Suwazono et al., 2006). They also considered other epide­
miological studies from Asia (mainly Japan and China) (Jin et al., 2004;
Kobayashi et al., 2006; Shimizu et al., 2006; Wu et al., 2001), but ulti­
mately based the MRL on the female dataset from the European studies

4
C. Wong et al.
as it resulted in the most conservative values. Using cadmium concen­
trations in urine, a Benchmark Dose (BMD) of 0.5 μg Cd/g creatinine was
obtained, equating to 0.33 μg/kg/day Cd intake. An uncertainty factor
of 3 was applied for human variability.
JECFA reviewed the same 35 epidemiological studies as the ATSDR
but included all 35 studies in its analysis covering both European
(Sweden, Belgium, France, Poland, Czech Republic) (Buchet et al., 1990;
de Burbure et al., 2006; Suwazono et al., 2006) and Asian countries
(Japan, China) (Kobayashi et al., 2006; Shimizu et al., 2006; Wu et al.,
2001). The endpoints measured were β-2MG, a low molecular weight
protein indicative of renal damage, and cadmium concentrations in
urine of adults over 50. The BMD chosen was 5.24 μg Cd/g creatinine,
equating to 0.8 μg/kg/day dietary cadmium from the lower bound
confidence interval. No uncertainty factors were applied as the tox­
icodynamic variabilities were accounted for in the model. EFSA set a
PTWI of 2.5 μg/kg/week (0.36 μg/kg/day) in 2009, which was reaf­
firmed in 2011 (EFSA, 2012a). The EFSA analysis utilized the same 35
epidemiological study database, but differences in selection of model for
data fit (biexponential for JECFA and Hill model for EFSA) and uncer­
tainty factors resulted the lower PTWI.
Among the more recent analyses, the ATSDR MRL produced the
lowest reference value, but it is based only on data from European fe­
males and excludes data from the Asian epidemiological studies, which
constituted the bulk of the database (93.5% of the individuals). Analyses
by JECFA and EFSA that made use of the entire 35 study database
produced higher reference values, suggesting that the ATSDR MRL may
be more conservative than is necessary. Consistent with the preference
for values derived by U.S. regulatory agencies as stated in the Methods
section, the EPA reference dose of 1 μg/kg/day was selected for the
updated tool, although it is noted that this value is not substantially
different than the more recent JECFA reference value of 0.83 μg/kg/day
that draws upon a larger database.
4.2. Cadmium background exposure levels from food and water
Critical studies concerning the level of cadmium intake from dietary
food consumption have been published. JECFA in 2013 determined
cadmium consumption to be 0.14–0.18 μg/kg/day in the United States
based on the FDA TDS from 2004 to 2008 in combination with the
NHANES WWEIA information from 2003 to 2006 (JECFA, 2013). A
study by Kim et al. (2019) showed a lower value of 0.07 μg/kg/day
cadmium for adults. The values Kim et al. (2019) derived for total
population daily cadmium intake could be lower than JECFA’s due to
limiting their dataset to exact TDS matches in the NHANES WWEIA
survey, which would not account for consumption of unmatched food
items. In contrast, a recent study by Spungen (2019) incorporated all
WWEIA food items to a TDS food item, thus accounting for total con­
sumption of the population by not limiting their dataset and taking into
account all food items consumed. In this study, which focused on cad­
mium and lead levels in children aged 1–6 years old, consumption data
from NHANES WWEIA 2009–2014 were mapped to the most current
TDS from 2014 to 2016. The TDS study also utilized inductively-coupled
plasma mass spectrometry (ICP-MS), which is more sensitive than the
atomic absorption spectrometry (AAS) utilized in previous TDS studies.
The cadmium background exposure level for children ranged from 0.38
to 0.43 μg/kg/day. While the recent Spungen (2019) study has a number
of strengths, it focused only on children up to the age of 6 years. Default
inputs to the HMST are based on adult consumption, however, custom
values can be entered in the tool where children specific dietary back­
ground values can be used. Therefore, adult values for daily cadmium
food intake values from JECFA (2013) were used as the default food
intake background level (Table 3). The cadmium intake estimated from
water does not appear to make up a large portion of the background
level (Table 3). The water limit for cadmium is the same for both the EPA
MCL and the FDA bottled water limit (5 μg/L/day); thus, the cadmium
water contribution was set to 0.08 μg/kg/day assuming an 80 kg adult
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consuming 1.2L of water. For children, the cadmium water consumption
would be 0.3 μg/kg/day assuming an 11 kg child consuming 0.6 L of
water per day.
4.3. Comparison of cadmium exposure with its reference value
Comparing the total U.S. background value of 0.26 μg/kg/day to the
EPA derived reference value of 1 μg/kg/day yields a margin of safety of
about 4. For children, the U.S. background value of 0.7 μg/kg/day
(combined between dietary and water intake) is still below the EPA
reference value of 1 μg/kg/day. The reference values for cadmium
considered similar studies and differ mainly due to exclusion of certain
regional groups, toxicokinetic modelling, and use of different uncer­
tainty factors. The value derived by the EPA (1 μg/kg/day) is similar to
the value derived by JECFA (0.8 μg/kg/day) which is more recent.
Considering that the most conservative values were found to be in
epidemiological studies based in several European countries, reference
values for specific regional groups may differ. This is evident in the low
ASTDR value of 0.1 μg/kg/day, which excluded epidemiological studies
in Asian countries and focused only on European epidemiological
studies.
5. Lead (Pb)
5.1. Lead reference values
Over the years, many agencies have found it difficult to identify or
maintain a reference value for lead due to a lack of a threshold value in
dose-response analyses. The difference between children and adult
sensitivities to lead is substantial, with cognitive effects in children
being the main reason for the lack of a safe threshold value. EPA
concluded in 1988 that it would be inappropriate to set an oral reference
dose for lead (EPA, 2004). In 2004, an oral reference dose was not set
because the changes seen in children’s neurobehavior “may occur at
blood levels so low as to be essentially without a threshold” (EPA, 2004).
Similarly, JECFA originally set a PTWI of 25 μg/kg/week (PTDI 3.57
μg/kg/day) in 1999. However, the PTWI was withdrawn in 2011 after it
was determined there were no safe levels for lead (JECFA, 2011b).
Presently, one of the few standing sources for reference values for
lead are the Interim Reference Levels (IRLs) set by the FDA in 2018,
which revised their IRL for children from 6 μg/day to 3 μg/day (Car­
rington and Bolger, 1992; FDA, 2018a). For women of child-bearing age,
the new recommendations were revised from 25 μg/day to 12.5 μg/day.
These new values were determined by the Toxic Elements Workgroup
created by the FDA in 2017 to tackle issues relating to toxic elements,
such as lead in foods. The Toxic Elements Workgroup also decided to
replace the term “Provisional Tolerable Total Daily Intake” (PTTDI) with
IRLs to better reflect the ongoing nature of the efforts to identify lead
level effects. The new interim reference values set by the FDA reflect
guideline changes made by the Center for Disease Control and Preven­
tion (CDC) to lower the “Blood Lead Reference Value” in children from
10 μg/dL to 5 μg/dL (CDC, 2012). Effects on neurodevelopment are still
the most sensitive endpoint at the BLL associated with the IRL, as other
endpoints (e.g., delayed puberty, cardiovascular effects, diabetes)
occurred at higher levels (Flannery et al., 2020). For this update, the
most recent FDA IRL values were used for children and adults.
5.2. Lead background exposure level from food and water
In the MDEST, the total background exposure was assumed to be
50% of the provisional total tolerable intake (PTTI) for the vulnerable
population and 33% of the PTDI for adults (Table 5). The default
background exposure level of lead of 0.11 μg/kg/day from food intake
for young children for the updated tool was based on work by Spungen
(2019) as it is the most recent dataset reviewed in young children (1-6
years-old), the background food intake level (hybrid mean) was 0.11
C. Wong et al.
μg/kg/day. This value was based on the most recent NHANES WWEIA
studies from 2009 to 2014 combined with recent FDA TDS studies from
2014 to 2016. Similarly, JECFA determined the background lead level
for 2-year-old children to be 0.11 μg/kg/day based on NHANES WWEIA
data from 2003 to 2006 and FDA TDS from 2004 to 2008 (JECFA, 2011).
The background exposure level for adults was determined to be 0.03
μg/kg/day based on work by JECFA (JECFA, 2011b).
Lead limits in drinking water differ among agencies. The FDA has a
bottled water limit for lead at 5 ppb while the WHO has a lead water
guideline at 10 ppb (FDA, 2019b; WHO, 2011b). The EPA has the
highest water limit with an MCL for lead at 15 ppb (EPA, 2019b). The
Maximum Contaminant Level Goal (MCLG) is set at 0 ppb (EPA, 2019b).
The main source of lead contamination in tap drinking water is through
corrosion of pipes that supply houses with water. Therefore, it is difficult
to determine and control the lead contamination on a national scale. The
EPA action limit for lead is not a health-based guidance value, but rather
a value that was deemed feasible for public water systems to control
levels of corrosion in pipes under the Lead and Copper Rule set in 1991
(EPA, 2008).
To gain a better understanding of the state of lead in drinking water
across the US, recent water quality reports from 15 major cities were
reviewed. The median level of lead was 5 ppb (90th percentile),
equating to 0.075 μg/kg/day for an 80 kg adult drinking 1.2 L of water
and 0.13 μg/kg/day for an 11.4 kg 1-year old child drinking 0.3 L of
water per day (Austin Water, 2017; City of Atlanta Department of
Watershed Management, 2018; City of Chicago Department of Water
Management, 2016; Denver Water, 2017; Department, 2017; District of
Columbia Water and Sewer Authority, 2019; Massachusetts Water Re­
sources Authority, 2015; Miami Dade Water and Sewer, 2018; New York
City Environmental Protection, 2013; Philadelphia Water Department,
2019; San Diego Public Utilities, 2018; San Francisco Public Utilities
Commission: Annual Water Quality Report, 2018, n.d.; Seattle Public
Utilities, n.d.; The City of Houston, 2017; The State Water Resources
Control Board Division of Drinking Water, 2018). (Table 3).
5.3. Comparison of lead exposure with its reference value
Conservative estimates for the total lead background exposure level
for both young children and adults using lead drinking water limits
exceeded their respective reference values recommended by the FDA.
For children, the background exposure level exceeded the reference
value by 0.38 μg/kg/day, while the background level for adults excee­
ded the reference value by 0.095 μg/kg/day. This is largely due to the
conservative nature of EPA’s estimated MCL for water contribution of
lead. However, actual drinking water levels of lead surveyed across 15
major U.S. cities reported values to be about 3-times lower than the
action limit set by the EPA. Using this value decreases the total back­
ground exposure level (0.11 μg/kg/day) below the FDA IRL for adults
(0.16 μg/kg/day). However, when considering children, the total lead
background exposure level with actual lead levels (0.24 μg/kg/day) is
just below the FDA interim reference level for young children (0.26 μg/
kg/day). Therefore, extra precaution should be taken when conducting
risk analysis for lead, especially for food and food products consumed
primarily by young children. Due to the continuing issue of lead expo­
sure in babies and young children, the FDA released its “Closer to Zero”
action plan in 2020 to help reduce exposure of lead and other metals of
concern (arsenic, cadmium, mercury) in this vulnerable population. The
action plan includes steps to continuously monitor lead levels in foods,
re-evaluate the IRL, and propose feasible action levels. Lead was prior­
itized above the other metals of concern, where Phase 1 of the plan
began in April 2021 (FDA 2021).
The reference value for lead for children (or lack thereof due to
withdrawal of the reference value) suggests that global regional differ­
ences would not affect the overall conclusion that lead levels from di­
etary consumption should be limited in young children and that there is
no significantly safe threshold level.
6
Regulatory Toxicology and Pharmacology 130 (2022) 105122
6. Mercury (Hg)
6.1. Mercury reference values
While there are many forms of mercury, methylmercury is the form
of most concern in the food supply. Based on toxicology ADME studies,
methylmercury can cross both placental and blood-brain barriers; as
such, sensitive endpoints focus on maternal intake of mercury and
subsequent neurodevelopmental effects in offspring (Antunes Dos San­
tos et al., 2016).
In 1999, the ATSDR set a methylmercury Minimum Risk Level (MRL)
at 0.3 μg/kg/day (ATSDR, 1999). This was based on the Seychelles Child
Development Study where inhabitants of the Seychelles Islands
consumed fish about 12 times per week (Davidson et al., 1998). The
study used several neurodevelopmental tests to measure cognitive and
motor development of children at 66 months. No adverse neuro­
developmental effects were measured in the study. A couple of years
later, the EPA set an oral reference dose of 0.1 μg/kg/day for mercury
(EPA, 2001). Epidemiological studies of mother-infant pairs were
reviewed from the Faroe Islands, Seychelles Islands, and New Zealand
(Davidson et al., 1998; Grandjean et al., 1997; Kjellström et al., 1986;
Kjellström et al., 1989). Neuropsychological effects of children 7 years
old were compared with cord blood mercury levels.
Internationally, JECFA derived a PTWI of 1.6 μg/kg/week (PTDI of
0.23 μg/kg/day) in 2007 based on a combination of both pivotal studies
from the Seychelles and Faroe Islands analyzed by the ATSDR and EPA,
respectively (Davidson et al., 1998; Grandjean et al., 1997; JECFA,
2008). EFSA took a similar approach to JECFA in 2012 to derive a PTWI
of 1.3 μg/kg/week (PTDI of 0.19 μg/kg/day) based on the same pivotal
studies used by JECFA, taking into account the effect of possible pro­
tective factors (i.e., poly-unsaturated fatty acids) (EFSA, 2012b).
The reference value used in the previous version of the tool was the
PTWI for inorganic mercury at 4 μg/kg/week (PTDI 0.57 μg/kg/day) set
by JECFA in 2011 (Table 4). This update to the tool focuses on the effects
of methylmercury as it is the more toxic form and most likely form of
exposure through foods. The oral reference dose set by the EPA (0.1 μg/
kg/day) was used as the default reference dose for the new metal
screening tool because of the more sensitive neurodevelopmental tests
administered as well as the use of cord blood which is a more direct
measurement of maternal blood mercury levels than levels present in
hair.
6.2. Mercury background exposure levels from food and water
A study by MacIntosh et al. (1996) used the Nurses’ Health Study and
Health Professionals Follow-Up Study and FDA TDS data from 1986 to
1991 to determine background mercury intake from food. In the Nurse’s
Health Study and Health Professionals Follow-Up Study, the food survey
portion is a mailed questionnaire that asks participants about their
previous year’s diet (MacIntosh et al., 1996). Based on this method, a
background methyl mercury level of 0.1 μg/kg/day was estimated. In
2002, Carrington and Bolger determined child and adult background
levels from seafood consumption only. The FDA TDS data (1992–1993),
National Marine Fisheries Survey (1978), and a study by Yess (1993)
were used as mercury residue studies for seafood only. The Continuing
Survey of Food Intake by Individuals (CSFII) from 1989 to 1991 was
used as the consumption database. Carrington and Bolger determined
that the background exposure level for children was 0.02 μg/kg/day
(2–5 years old) and 0.01 μg/kg/day for adults. Xue et al. (2012) deter­
mined a background exposure level for adults to be 0.03 μg/kg/day
children and 0.02 μg/kg/day adults. These values were derived from
NHANES WWEIA 1999–2006 and from FDA TDS 1990–2002.
A water limit for mercury of 6 μg/L was set by WHO in 2005 (WHO,
2005b). The EPA Maximum Contaminant Level and the FDA bottled
water limit both have current water limits set at 2 ppb (EPA, 2019b;
FDA, 2019b). Assuming an 80 kg adult drinking 1.2 L of water (EPA,
C. Wong et al.
2011), 0.03 μg/kg/day of mercury can be attributed to drinking water
sources.
The contribution of mercury from food and water to the total back­
ground mercury exposure is about equal (Table 3). The water limit is set
for inorganic mercury but can be assumed that it will be converted to
methylmercury by microorganisms in the water, which will bio­
accumulate up the food chain. The water limit for mercury set by WHO
in 2005 is three times higher than the current limits set by the EPA and
the FDA. The water contribution for the new tool was set to the current
EPA drinking water limit of 0.03 μg/kg/day for a total background
exposure level of 0.05 μg/kg/day. In contrast, Tran et al. (2015) chose to
use a total background exposure level of 0.127 μg/kg/day, with
contribution from food intake as 0.06 μg/kg/day (FDA TDS, 2001–2006)
and 0.067 μg/kg/day from water (FDA bottled water limit, 60 kg adult
consuming 2 L of water) (Tran et al., 2015) (Table 5).
6.3. Comparison of mercury exposure with its reference value
Comparing the U.S. dietary background value of 0.05 μg/kg/day and
an EPA derived reference value of 0.1 μg/kg/day demonstrates a two-
fold margin of safety. Reference values derived from various global
regulatory bodies utilize similar pivotal studies and resulted in similar
reference values and is not expected to be affected by regional differ­
ences. Background levels of methylmercury may differ between regional
groups due to cultural eating habits, such as increased consumption of
seafood that may be common in countries such as Japan. This may be
further affected if consumption of whale meat is incorporated into the
diet, such as in the Faroe Islands, and decrease the margin of safety.
7. Chromium (Cr)
7.1. Chromium reference values
While there are several states of chromium, the two most stable
forms are trivalent chromium [Cr (III)] and hexavalent chromium [Cr
(VI)] (EPA, 2010). The trivalent form of chromium is much less toxic
than the hexavalent form because it crosses the cell membrane with low
efficiency and is less likely to cause damage (ATSDR, 2012c). While
ingested hexavalent chromium is reduced to the less toxic trivalent
chromium in the GI tract, some can escape this process and enter cells,
where DNA damage can lead to cancer and other adverse health effects
(ATSDR, 2012c).
7.1.1. Cr(III) reference values
Trivalent chromium is needed for normal energy metabolism. While
the exact mode of action is unknown, it aids in insulin efficacy (National
Academy of Science Institute of Medicine, 2006). The EPA has set an oral
reference dose for trivalent chromium at 1.5 mg/kg/day in 1999 (EPA,
2010). This value was based on a long-term study in rats fed varying
concentrations of Cr2O3 in bread for 840 days with assessment of his­
tological changes (Ivankovic and Preussman, 1975). However, this
reference value was set with low confidence due to the lack of detail in
the study protocol as well as absence of supporting data in the literature
for high doses (EPA, 2010).
EFSA set a TDI of 0.3 mg/kg/day in 2014 based on a study in mice
and rats fed chromium picolinate, a popular form of trivalent chromium
used in dietary supplements, for 90 days or 2 years (EFSA, 2014).
Changes in reproductive endpoints were measured.
7.1.2. Cr(VI) reference values
Comparatively, reference values for hexavalent chromium differ
greatly from the reference value set for trivalent chromium. An EPA oral
reference dose of 3 μg/kg/day was set in 1998 based on a study of rats
ingesting K2CrO4 in water for one year (EPA, 1998; MACKENZIE et al.,
1958). Adverse effects noted included pathologic changes in blood and
other tissues. In 2012, the ATSDR set a MRL at 0.9 μg/kg/day (ATSDR,
7
Regulatory Toxicology and Pharmacology 130 (2022) 105122
2012). This was based on F344 rats and BCC3F1 mice ingesting water
with sodium dichromate for 2 years (NTP, 2008) and the observation of
diffuse epithelial hyperplasia of the duodenum. Recently, Health Canada
developed a reference value of 2.2 μg/kg/day in 2018 (Health Canada,
2018). This was based on a 90-day sodium dichromate dihydrate water
study in B6C3F1 mice (Thompson et al., 2011). Small intestine hyper­
plasia and small intestinal tumors were observed as critical effects.
7.2. Chromium background levels from food and water intake
Dietary background for chromium is measured either as total chro­
mium or as trivalent chromium. A study by Kumpulainen et al. (1979)
determined a total chromium daily intake for US adults to be 76 μg/day.
Assuming an 80 kg adult, that is 0.95 μg/kg/day (EPA, 2011). This value
was based on a study examining high and low-fat content in typical
American diets. The Institute of Medicine determined an Adequate
Intake of 0.43 μg/kg/day for trivalent chromium, which is the “level at
which most Americans intake” (National Academy of Science Institute of
Medicine, 2006). This value was derived from NHANES 1988–1994 data
with information from Anderson et al. (1992) that determined 13.4 μg of
trivalent chromium was ingested for every 1,000 kcal (Anderson et al.,
1992). A study in 2002 determined a total chromium intake of 0.47
μg/kg/day using databases such as CSFII and the FDA TDS studies from
1982 to 1994 (Moschandreas et al., 2002).
Water limits are also typically reported as total chromium. It is
difficult to differentiate between trivalent chromium and the more toxic
hexavalent chromium because the forms can interchange (ATSDR,
2012). While hexavalent chromium is more soluble in water, the effect
of the environment determines the more predominant form. The water
guideline set by WHO in 2005 was 0.05 mg/L (WHO, 2005a). The FDA
and EPA both set their water limits to 0.1 mg/L for total chromium (EPA,
2019b; FDA, 2019b). Assuming an 80 kg adult drinking 1.2 L of water
per day, that is 1.5 μg/kg/day (EPA, 2011).
The difference in reference values between trivalent and hexavalent
chromium is dependent on the difference in the relative toxicity.
Trivalent chromium is less toxic than hexavalent chromium, which ex­
plains why the trivalent chromium reference value is magnitudes higher
than the one for hexavalent chromium.
In the MDEST, the reference value for Cr(III) was set to 250 μg/day
based on WHO recommendations for Cr(III) supplements in 1996
(Table 4). For Cr(VI), the value used was a proposed EPA oral reference
dose of 0.0009 mg/kg/day in 2010. This value is the same value that the
ATSDR set in 2012. However, the proposed EPA oral reference dose of
0.0009 mg/kg/day has not been finalized.
Studies examining background exposure levels of chromium from
food or water intake are usually expressed as total chromium because it
is difficult to determine chromium speciation. The value derived by
Kumplulainen in 1979 was relatively the highest value (0.95 μg/kg/
day), about two times higher than the value determined by the Institute
of Medicine or Moschandreas et al. The study by Kumplulaeinen et al. is
relatively dated and the methodology was not as extensive as it could be
using a large database such as the FDA TDS or NHANES WWEIA dataset.
The exposure-background level of 0.47 μg/kg/day for total chromium
determined by Moschandreas is similar in value to that determined by
the Adequate Intake level of 0.43 μg/kg/day for trivalent chromium set
by the Institute of Medicine. Because the values are so similar, this
suggests that most chromium found in foods is the less toxic trivalent
form.
Most of the total background exposure level for total chromium
comes from water sources. The EPA limit set for total chromium is quite
high at 0.1 mg/L.
7.3. Comparison of chromium exposure with its reference value
The FDA’s focus on heavy metals (toxic elements) excludes chro­
mium (“Metals. FDA,” 2019) and this is supported by the general lack of
C. Wong et al.
chromium present in samples monitored along the food supply. The
USDA Food Safety Inspection Service (FSIS) routinely screens animal
products for various metals such as chromium. Of the 3,013 samples
analyzed for total chromium, between 2013 and 2017, only one positive
sample was detected (USDA-FSIS (US Department of Agriculture Food
Safety Inspection Service), 2013–2017).
Even if the more toxic form of chromium (CrVI) were to hypotheti­
cally contaminate food, conversion to the non-toxic trivalent chromium
form reduces exposure. Reducing agents naturally present in many foods
would be the first step of reduction to trivalent chromium (National
Academy of Science Institute of Medicine, 2006). Once ingested, further
reduction of hexavalent chromium to trivalent chromium occurs in the
GI tract (Sun et al., 2015). Exposures to the more toxic hexavalent form
of chromium seems unlikely and chromium (III and VI) is not listed as a
priority heavy metal of concern with the FDA Toxic Elements Working
Group, therefore, trivalent and hexavalent chromium were removed
from the HMST and were not assigned a default reference or background
exposure value.
8. Consideration of carcinogenicity of metals in foods
This work focuses solely on non-cancer-based health endpoints. In
addition to non-cancer endpoints, some metals that were reviewed in
this work may be carcinogenic and have defined cancer slope factors
(arsenic, chromium VI). For arsenic, the EPA has set an oral cancer slope
factor of 1.5 (mg/kg/day)− 1 in 1995 due to skin, lung, and bladder
cancer endpoints following chronic oral exposure (EPA, 1998). For
hexavalent chromium, the EPA has not been able to determine a cancer
slope factor for chromium (VI) by the oral route of exposure (EPA,
2019d). However, in 2011 the California Office of Environmental Health
Hazards Assessment (OEHHA) determined a hexavalent cancer slope
factor of 0.5 (mg/kg/day)− 1 (Office of Environmental Health Hazard
Assessment California Environmental Protection Agency, 2011).
Assuming an acceptable excess cancer of risk of 1 in 1 million, the safe
cancer exposure levels would be 0.007 μg/kg/day and 0.0002
μg/kg/day for arsenic and chromium (IV), respectively. These safe
cancer threshold levels are significantly lower than their respective
background exposure levels, which can be more than 25 times less than
the average amount of the metal consumed from food and water on a
daily basis. Therefore, it is not feasible to use cancer-based reference
doses in a screening-level risk assessment tool such as the HMST. Further
refined risk assessments should be considered for meals with defined
cancer slope factors.
9. Conclusions
Screening tools such as the HMST, based on relevant reference values
and background exposure levels, can greatly facilitate rapid, tier-1 risk
assessments of the potential risks of heavy metals in food and food in­
gredients. This work presents a review of current reference values and
total U.S. based background exposure levels for heavy metals that are of
concern in the food supply as an update to improve the tool. Overall, the
total background exposure values for most heavy metals of concern in
the food supply (cadmium, mercury, and arsenic) were found to be
below the safe U.S. regulatory reference values. However, this was not
the case for lead, where combined intake from food and water was
nearly equivalent to the most recent reference values set by the FDA for
young children. The minimal exposure of chromium (CrIII and CrVI) in
foods suggest it is not a wide-spread public health concern and was
subsequently removed from the tool.
There are limitations to this analysis and selection process that
should be acknowledged. First, geographical and cultural factors can
profoundly influence exposure to these metals in foods. The extensive
data on food content, drinking water quality, and consumption rates
available for the U.S., as well as the European Union, greatly facilitates
this kind of study. However, the conclusions drawn cannot be assumed
8
Regulatory Toxicology and Pharmacology 130 (2022) 105122
valid for other parts of the world. The framework of the model allows for
inputs tailored to different regions and cultures instead of the defaults,
but a discussion of specifics was beyond the scope of this review.
Additionally, this work focused solely on exposure due to daily dietary
intake. This does not take into account other sources of exposure outside
of daily food consumption such as exposure to contaminated sites or
other episodic acute exposures. Routes of exposure aside from oral
ingestion, such as inhalation or dermal contact, may also contribute to
total body burden of these heavy metals. Together, these factors may
increase the total background value and possibly exceed safe reference
values. This may be especially true for heavy metals such as lead, where
there is a very small margin of safety between daily consumption and
safe reference values, where the addition of extraneous sources of lead
can lead to higher risk to health. Finally, as discussed in Section 8, the
omission of a direct consideration of carcinogenicity is a major limita­
tion, especially for metals with strong evidence of carcinogenicity in
humans such as arsenic.
As this review demonstrates, metal reference values and background
levels will likely continue to evolve in response to emerging science, new
health endpoints, and changes in food consumption trends, highlighting
the need for updates for tools used by risk assessors.
Funding body information
This work was supported by the Institute for the Advancement of
Food and Nutrition Sciences (IAFNS) through an ILSI North America
Food and Chemical Safety Committee Summer Fellowship awarded to
CW.
Declaration of competing interest
The authors declare the following financial interests/personal re­
lationships which may be considered as potential competing interests:
The authors declare the following which may be considered as po­
tential competing interests: CW was employed by ILSI North America
during the conduct of this research. SMR served as academic advisor to
the ILSI North America Food and Chemical Safety committee between
2014 and 2019. INS was employed by ILSI North America and is
currently employed by IAFNS.
Acknowledgements
This work was supported by the Institute for the Advancement of
Food and Nutrition Sciences (IAFNS) through an ILSI North America
Food and Chemical Safety Committee Summer Fellowship awarded to
CW. IAFNS is a nonprofit science organization that pools funding from
industry collaborators and advances science through the in-kind and
financial contributions from public and private sector participants.
https://iafns.org/
The authors are grateful for Khatera Rahmani at Mars Rigley, Jieun
Lee at CJ Foods, and members of the IAFNS Food and Chemical Safety
Committee for their technical support during CW’s fellowship and
conduct of the project.
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