United States
Environmental Protection
1=1 m m Agency
EPA/690/R-11/027F
Final
3-01-2011
Provisional Peer-Reviewed Toxicity Values for
Inorganic Phosphates
(Orthophosphoric Acid and Inorganic Phosphate
Compounds, Including Ortho- and
Condensed Phosphates)
(Various CASRNs included in the text)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Custodio V. Muianga, PhD, MPH
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Anuradha Mudipalli, MSc, PhD
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS ii
BACKGROUND 3
HISTORY 3
DISCLAIMERS 3
QUESTIONS REGARDING PPRTVS 4
INTRODUCTION 4
OCCURRENCE, HOMEOSTASIS, AND DIETARY REQUIREMENTS 5
REGULATORY ACTIVITY REGARDING THE TOXICITY OF INORGANIC
PHOSPHATES 7
LITERATURE SEARCH 8
REVIEW 01 PERTINENT DATA 9
HUMAN STUDIES 01 ORAL EXPOSURE 9
SHORT-TERM, SUBCHRONIC-DURATION, AND CHRONIC-DURATION ANIMAL
STUDIES 11
Subchronic Toxicity of Inorganic Phosphates 12
Chronic Toxicity of Inorganic Phosphates 13
STP 13
SUMP 13
DEVELOPMENTAL STUDIES 14
REPRODUCTIVE TOXICITY 14
DERIVATION OF SUBCHRONIC AND CHRONIC p-RfD VALUES FOR
PHOSPHORUS FROM INORGANIC PHOSPHATES 15
p-RfD CALCULATED FROM WEINER ET AL. (2001) 15
p-RfD CALCULATED I ROM IOM (1997) 18
p-RfD CALCULATED I ROM NORDIN (1988) 18
RATIONALE FOR SELECTION OF THE BEST APPROACH (OPTION 3) FOR
DERIVING SUBCHRONIC AND CHRONIC p-RlDs 21
DERIVATION 01 CHRONIC p-RfC 22
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR INORGANIC
PHOSPHATES 23
WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 23
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK 23
REFERENCES 24
APPENDIX A. DATA TABLES 31
l
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COMMONLY USED ABBREVIATIONS1
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELhec
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
1 Table A.l provides a list of inorganic phosphate compounds and their acronyms.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
INORGANIC PHOSPHATES (ORTHOPHOSPHORIC ACID AND INORGANIC
PHOSPHATE COMPOUNDS, INCLUDING ORTHO- AND CONDENSED
PHOSPHATES) (VARIOUS CASRNS INCLUDED IN THE TEXT)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1) EPA's Integrated Risk Information System (IRIS)
2) Provisional Peer-Reviewed Toxicity Values (PPRTVs) used in EPA's Superfund
Program
3) Other (peer-reviewed) toxicity values, including
~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR);
~ California Environmental Protection Agency (CalEPA) values; and
~ EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's IRIS. PPRTVs are developed according to a Standard
Operating Procedure (SOP) and are derived after a review of the relevant scientific literature
using the same methods, sources of data, and Agency guidance for value derivation generally
used by the EPA IRIS Program. All provisional toxicity values receive internal review by a
panel of six EPA scientists and external peer review by three independently selected scientific
experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram
consensus review provided for IRIS values. This is because IRIS values are generally intended
to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund
Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a 5-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV documents conclude that
a PPRTV cannot be derived based on inadequate data.
DISCLAIMERS
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and Resource Conservation and Recovery Act (RCRA) program offices are advised to
carefully review the information provided in this document to ensure that the PPRTVs used are
appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility
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in question. PPRTVs are periodically updated; therefore, users should ensure that the values
contained in the PPRTV are current at the time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV document and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
The focus of this document is on the development of oral p-RfD values to be used in
assessing health risks associated with the ingestion of inorganic phosphates in water. Any other
exogenous cumulative inorganic phosphate from dietary sources or enriched phosphate products
needs to be taken into account during toxicity assessment of inorganic phosphorus in water. This
analysis does not include elemental phosphorus in any form due to the fact that human exposure
to elemental phosphorus in a typical environmental setting is unlikely to occur (elemental
phosphorus [P] has a very short half-life in water) and because the toxicity of elemental
phosphorus is much higher than that of inorganic phosphorus compounds, to which individuals
are more likely to be exposed. Phosphorus is most commonly found in nature in its pentavalent
o _
form in combination with oxygen, as phosphate (PO4 ). Phosphorus (as phosphate) is an
essential constituent of all known protoplasm, and its content is quite uniform across most plant
and animal tissues. Orthophosphate is the basic unit for all phosphates. Orthophosphate can
form many polymeric ions or condensed phosphates (pyro-, meta-, and other polyphosphates).
Inorganic phosphates (ortho- and condensed phosphate anions) can be grouped into four classes
based on their cations including monovalent cations (sodium, potassium, and hydrogen), bivalent
cations (calcium and magnesium), ammonium, and aluminum. The phosphoric acids have been
grouped with the other monovalent cations based on valence state. There are about 30 chemicals
with inorganic phosphate as an anion. Figure 1 shows the basic structure of ortho- and
condensed phosphates, and Appendix A, Table A.l presents a list of ortho- and condensed
phosphate names, their CASRNs, and acronyms for each compound. The classification scheme
is based on the similar chemical and toxicological properties of inorganic phosphates within a
given class. In each class, ortho- and condensed phosphate salts are grouped together. This
secondary grouping is based on the chemicals' similar toxicological properties and on the fact
that in vivo, condensed phosphates break down into orthophosphates. Thus, ortho- and
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condensed phosphate salts can be viewed as having commonality by their cations (Weiner et al.,
2001; WHO, 1982). In this document, "statistically significant" denotes a/rvalue of <0.05.
Phosphate anion:
0
. II .
O—P 0
1
0
Dimer:
0
II
MO P —0
1
OM
Trimcr
0 0 0
II II II
MO P O P O P OM
1 I I
OM OM OM
Polyphosphates ¦ Mfn.;,P,0|
K«y: M - uittal or hydrogen atom
O - oxygen aiom
P - plmsphorns ;iieir
Figure 1. Basic Structure of Ortho- and Condensed Phosphates (Weiner et al., 2001)
OCCURRENCE, HOMEOSTASIS, AND DIETARY REQUIREMENTS
Phosphorus homeostasis and dietary requirements must be considered alongside toxicity
studies to determine appropriate toxicity values. It is atypical for a healthy individual to have a
deficiency in phosphorus because (1) phosphorus is readily available through ingestion of most
food sources and (2) endogenous phosphorus is recycled indefinitely (IOM, 1997). Phosphorus
is readily bioavailable from all foods except seeds (i.e., beans, peas, unleavened cereals, nuts).
Seeds contain phosphorus in the form of phytic acid, which can only be released in the presence
of phytase; phytase is found in intestinal bacteria and in certain foods. Gastrointestinal (GI)
absorption of phosphorus is 55-70% in adults and 65-90% in children, and it does not vary by
diet (except for those high in phytic acid) or with phosphorus dosage up to 3 g (100 mmol)/day.
Aluminum and unabsorbed calcium in the GI tract (such as calcium carbonate from antacids)
inhibit phosphorus absorption through complex formation.
In humans, 85% of the endogenous phosphorus is bound together with oxygen and
calcium in the form of crystalline hydroxyapatite [CasfPO^OH)] in bone (Lewis, 2009a).
Most of the remaining phosphorus is found in the form of organic phosphate in the intracellular
compartment of soft tissues (e.g., adenosine diphosphate, adenosine triphosphate, nucleic acids,
and membrane phospholipids). A small fraction of the total phosphorus is also found in plasma
as inorganic phosphate. The small plasma inorganic phosphate compartment is critical to the
tightly interrelated homeostasis of phosphate and calcium in bone and soft tissue.
o
II
-P OM
OM
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Unlike calcium, phosphorus concentration in the plasma is only loosely regulated (IOM,
1997) and is primarily a function of phosphorus intake. Increases in plasma inorganic
phosphorus can result in increased parathyroid hormone (PTH) secretion (leading to decreased
renal resorption of phosphorus2, increased bone resorption, and, potentially, increased plasma
calcium) and decreased 1,25-dihydroxy vitamin D (leading to decreased transport of calcium
from the intestine, and, potentially, decreased plasma calcium). According to IOM (1997), these
changes are not adverse when calcium intake is adequate. The normal range of inorganic
phosphate concentrations in the plasma of an adult human is 2.5-4.5 mg/dL (0.81-1.45 mmol/L)
(Lewis, 2009a). Levels are 50% higher in infants and 30% higher in children. In adults,
hypophosphatemia4 is considered to occur when plasma phosphate concentrations fall below
2.5 mg/dL; hyperphosphatemia5 is defined by plasma phosphate concentrations that exceed
4.5 mg/dL.
Plasma calcium concentration is more stringently regulated than phosphorus
concentration. It is controlled primarily by PTH and vitamin D, and secondarily by calcitonin
(Lewis, 2009b). Normal total plasma concentrations of calcium in an adult human are in the
range of 8.8-10.4 mg/dL (2.0-2.6 mmol/L). Hypocalcemia is defined by total plasma calcium
concentrations <8.8 mg/dL; hypercalcemia is defined by total plasma calcium concentrations that
exceed 10.4 mg/dL (Lewis, 2009b).
The product of the plasma calcium and phosphate (Ca x PO4) concentrations is an
important determinant of soft-tissue calcification. When the Ca x PO4 product exceeds
70 mEq/L, precipitation of CaPC>4 crystals in soft tissue is more likely to occur; a value of
60 mEq/L is considered to be normal (Lewis, 2009b). However, calcification of vascular tissue
may occur at Ca x PO4 values as low as 55 mEq/L in patients with chronic renal disease.
The Food and Nutrition Board of the Institute of Medicine (IOM, 1997) has published the
following recommended daily allowances (RDAs) for phosphorus:
• Children 1-3 years: 460 mg (14.8 mmol) P/day
• Children 4-8 years: 500 mg (16.1 mmol) P/day
• Adolescents 9-18 years: 1250 mg (40.3 mmol) P/day
• Men and women 19->70 years: 700 mg (22.6 mmol) P/day
2Phosphorus is excreted primarily through the kidneys (IOM, 1997). It is filtered out of the plasma in the
glomerulus and resorbed in the proximal tubules. The rate of resorption is limited and can be described by the
tubular maximum for phosphate (TmP), which is inversely proportional to PTH concentration: high plasma
phosphorus results in high PTH and reduced TmP (less phosphorus is resorbed).
3Vitamin D (calciferol, includes both D2 and D3 forms) must be converted to its biologically active form
(1,25-dihydroxy vitamin D) by two hydroxylations that occur in the liver and kidney (IOM, 1997). 1,25-Dihydroxy
vitamin D regulates intestinal absorption of calcium and phosphorus.
4Fairly rare condition that may occur in hospitalized patients receiving parenteral feeding, burn patients, acute
alcoholism, recovery phase of diabetic ketoacidosis, severe respiratory alkalosis, hyperparathyroidism, long-term
administration of antacids or diuretics, or following prolonged malnutrition (Lewis, 2009a).
5Occurs as a result of decreased renal excretion of phosphate; some causes are glomerular filtration rate
<30 mL/minute as in chronic renal failure, hypoparathyroidism, pseudohypoparathyroidism, excessive oral
phosphate administration, overzealous use of enemas containing phosphate, or shifts of phosphate into the
extracellular space in end-stage disease states or overwhelming systemic infection (Lewis, 2009a).
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As determined by IOM (1997), the values for children are based on concentrations
believed to be necessary for adequate bone and soft tissue growth, and the values for adults are
based on the concentrations necessary for normal plasma inorganic phosphate concentrations.
Due to the lack of evidence for increased phosphorus demand during pregnancy and lactation,
the RDA values for pregnancy and lactation are the same as the age-based requirements,
according to IOM (1997). These values are considered to be adequate for residents of the United
States and Canada. Phosphorus deficiency is typically seen only in cases of acute alcoholism,
chronic malnutrition, diabetic ketoacidosis, kidney disease, advanced cancer, or hospitalized
patients fed parenterally (Lewis, 2009a).
REGULATORY ACTIVITY REGARDING THE TOXICITY OF INORGANIC
PHOSPHATES
No oral RfD is available on the EPA IRIS database for inorganic phosphate;
orthophosphoric acid; or any of the calcium, sodium, potassium, or magnesium salts (U.S. EPA,
2009). Similarly, no values are available for any of these compounds on the Drinking Water
Standards and Health Advisories list (U.S. EPA, 2006) or the HEAST database (U.S. EPA,
1997). EPA (1989) reviewed the health effects of inorganic phosphorus compounds but did not
derive toxicity values. There are no other EPA documents having the ability to inform toxicity
value derivation for inorganic phosphates included in the Chemical Assessments and Related
Activities (CARA) list (U.S. EPA, 1991, 1994).
Orthophosphoric acid and inorganic phosphate salts are used as food ingredients and are
considered to be Generally Recognized as Safe (GRAS) by the Food and Drug Administration
(U.S. FDA, 1979). The toxicity of orthophosphoric acid or its sodium, calcium, or potassium
salts has not been reviewed by ATSDR (2009). The World Health Organization (WHO, 1971,
1965) reported that a 375-mg P/kg body-weight6 was a "level causing no significant
toxicological effect in the rat" based on a 90-week study of three generations in rats (Bonting and
Jansen, 1956) and estimated a maximum tolerable daily intake (MTDI) for humans of 70 mg
P/kg from all sources of phosphorus (JECFA, 2009; WHO, 1982). It is important to note that
MTDI is not an acceptable daily intake (ADI); rather, it applies to the sum of phosphate additives
and phosphates that occur naturally in food. The MTDI is based on an assumption of adequate
dietary calcium; WHO (1982) notes that if calcium intake were higher, then the intake of
phosphate could be proportionately higher; if calcium intake were lower, then the intake of
phosphate that could be tolerated would be proportionately lower.
The IOM (1997) derived Tolerable Upper Intake Levels (ULs) for dietary phosphorus as
follows:
Children 1-8 years: 3 g (96.8 mmol) P/day
Adolescents 9-18 years and adults 19-70 years: 4 g (130.0 mmol) P/day
Adults >70 years: 3 g (96.8 mmol) P/day
Pregnancy 14-50 years: 3.5g(112.9 mmol) P/day
Lactation 14-50 years: 4.0 g (130.0 mmol) P/day
6This value is based on a NOAEL of 7500 mg P kg-day of orthophosphoric acid in the diet; 375 mg P kg-day is the
WHO estimate of the equivalent dose of phosphorous.
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For infants, IOM (1997) did not derive a UL but recommended that the source of phosphorus
intake should be solely food and breast milk or formula (the phosphorus content of cow's milk is
too high and results in hypocalcemia in approximately 30 out of 10,000 neonates).
The IOM (1997) UL values are based on the empirical relationship between phosphorus
intake and serum phosphorus concentrations established in adult volunteers (Nordin, 1988) and
in infants and young children. In adults, assuming 65% GI absorption, the upper boundary for
oral intake associated with the upper boundary for normal serum inorganic phosphorus is 3.4 g
(110 mmol)/day. Given that serum phosphorus values in infancy are naturally much higher than
adult values and are safe, and that there is no reason to assume major differences in critical
toxicity (i.e., metastatic mineralization) at different ages, IOM (1997) used the regression
equation for adult intake versus serum concentration along with the upper boundary for infant
serum value to project an equivalent adult intake of >10.2 g (330 mmol)/day. Thus, the adult UL
value is based on a predicted NOAEL of 10.2 g/day. In deriving the UL value, the point of
departure (POD) of 10.2 g/day was divided by an uncertainty factor (UF) of 2.5; the partial UF
accounts for possible interindividual differences in pharmacodynamics, given that the
relationship between intake and serum concentration is known. The UL for children 1-8 years
old is based on the POD of 10.2 g/day divided by a UF of 3.3 to account for potentially increased
susceptibility associated with smaller body size. The UL for adults over the age of 70 years is
based on the POD of 10.2 g/day divided by a UF of 3.3 because IOM felt that it was prudent to
lower the value to account for the increasing prevalence of impaired renal function. IOM (1997)
did not offer any specific numerical evidence to support this decision. The UL for pregnancy is
based on an observation that the absorption efficiency of phosphorus increases by 15% in
pregnancy, and therefore, the intake associated with the upper end of the normal range for serum
phosphorus would be approximately 3.5 mg (112.9 mmol)/day. Given that the phosphorus
economy of a lactating woman is not discernibly different from a nonlactating woman, IOM
(1997) assumed the upper limit was to be the same as for a nonlactating woman.
A cancer assessment for orthophosphoric acid or other inorganic phosphates is not
available on the IRIS database (U.S. EPA, 2009), the Drinking Water Standards and Health
Advisories list (U.S. EPA, 2006), or the HEAST database (U.S. EPA, 1997). The carcinogenic
potential of orthophosphoric acid or other inorganic phosphates has not been studied or reviewed
by the National Toxicology Program (NTP, 2009, 2005), the International Agency for Research
on Cancer (IARC, 2009), or CalEPA (2009).
LITERATURE SEARCH
Literature searches were conducted from 1960s through September 16, 2010 for studies
relevant to the derivation of provisional toxicity values for orthophosphoric acid. Databases
searched include the following: MEDLINE, TOXLINE (with NTIS), BIOSIS,
TSCATS/TSCATS2, CCRIS, DART, GENETOX, HSDB, RTECS, Chemical Abstracts, and
Current Contents (last 6 months). Additional searches of PubMed (through August 17, 2009)
were conducted to establish the availability of studies relevant to sodium and potassium salts of
orthophosphoric acid, including dibasic sodium phosphate (Na2HP04), dibasic potassium
phosphate (K2HPO4), monobasic sodium phosphate (NaFbPOzt), and monobasic potassium
phosphate (KH2PO4), as well as mono-, di-, and tricalcium phosphate, trisodium and tripotassium
phosphate, ammonium phosphate (mono- and di-), magnesium phosphate (mono- and di-),
phosphate (restricted to exclude phosphine, organic phosphates, and organophosphate
pesticides), and phosphorus (restricted to exclude phosphorus pentoxide, phosphorus trichloride
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and pentachloride, elemental phosphorus, etc.). Elemental phosphorus was excluded from
consideration because of its short half-life in water and resultant transformation to phosphate.
The IOM (1997) Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D,
and Fluoride was searched for additional relevant citations.
REVIEW OF PERTINENT DATA
Based on the existing human and animal studies, the primary concerns for
phosphate-induced toxicity are disruption of calcium economy, soft-tissue mineralization, and
kidney damage. Disruption of calcium economy is the most commonly observed effect of
phosphate ingestion in both humans and animals. While soft-tissue mineralization and kidney
damage are common consequences of phosphate ingestion in laboratory animals, these changes
are rare in humans, occurring most often (but not exclusively) in people who are already in
end-stage kidney failure or other chronic disease states (IOM, 1997; Nordin, 1988).
HUMAN STUDIES OF ORAL EXPOSURE
The primary types of human studies encountered in the literature include studies of
dietary supplementation and their effects on calcium balance, studies of the use of
phosphate-containing solutions that are administered in high doses to cause bowel evacuation
prior to surgery or colonoscopy, and carbonated beverage consumption studies. The carbonated
beverage studies are potentially relevant because phosphoric acid is commonly used as an
acidifying agent, particularly in cola beverages. There are also many studies of calcium and
phosphorus balance in patients with end-stage chronic kidney disease. Following are summaries
of these findings.
Controlled Supplementation or Dietary Studies that Assess Effects on Calcium Balance
There have been many studies designed to assess the effects of phosphorus
supplementation or deficiency on the calcium economy. Appendix A, Table A.2 summarizes
key studies of this type. The common finding of these studies is that increased dietary phosphate
can cause small—but statistically significant—decreases in serum calcium (<3%), small (2-fold
or less)—but statistically significant—increases in serum PTH or markers for PTH (e.g., urinary
cAMP), and small—but statistically significant—increases in markers for bone resorption
(Kemi et al., 2009, 2008; Calvo et al., 1990, 1988; Zemel and Linkswiler, 1981). Increasing
dietary calcium appears to mitigate the changes produced by administration of high phosphate
alone (Kemi et al., 2008; Zemel and Linkswiler, 1981; Heaney and Nordin, 2002). The
aforementioned studies reported exposure durations from 24 hours (Kemi et al., 2008;
Calvo et al., 1988) to 6 weeks (Grimm et al., 2001). Kemi et al. (2009) is a cross-sectional study
of premenopausal females that relied upon 4-day food records from which dietary phosphorus
and calcium intakes were calculated; subjects were sorted into quartiles based on phosphorus
intake, and the first and fourth quartiles were compared. This and the studies by Calvo et al.
(1990, 1988) are the only studies that reported significant decreases in serum calcium.
One 10-day study that used a high dietary phosphorus concentration of 1600 mg P/day
with adequate dietary calcium found no significant effects on serum PTH or bone resorption
(Bizik et al., 1996). The study using the highest dietary phosphorus concentration
(3008 mg/day) and adequate-high dietary calcium (1700-1995 mg/day) for the longest duration
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of exposure (6 weeks) found no significant changes in serum PTH, bone resorption, or indicators
of renal function (Grimm et al., 2001) in healthy young women, who appear to be more sensitive
to these effects than young men (Calvo et al., 1988). Intestinal upsets including soft stools and
mild diarrhea were observed in all subjects during the period of high-phosphorus exposure
(Grimm et al., 2001). These effects are likely due to bolus dosing (high phosphorus was
achieved with supplemental tablets administered with orange juice, rather than through food
sources); as discussed below, inorganic phosphate tablets are used for bowel cleansing. Studies
designed specifically to assess calcium balance found no consistent critical effects of increased
dietary phosphate on calcium balance in either males or females (Heaney and Recker, 1982;
Spencer et al., 1978). According to WHO (1971) and Schrodter et al. (1991), a study (published
in German) on ingestion of phosphoric acid reported that no marked urinary changes indicative
of a detrimental effect on metabolism were seen in students who drank 2000-4000 mg P/day for
10 days (29-57 mg P/kg-day) or 3900 mg P/day for 14 days (56 mg P/kg-day) in fruit juices
(Lauerson, 1953). Doses in parentheses were calculated assuming a 70-kg body weight in
accordance with EPA (1988).
Studies of the Use of Phosphate-containing Solutions Administered as Bowel-Cleansing
Agents
Sodium phosphate is commonly used as a bowel-cleansing agent prior to diagnostic
imaging and surgical procedures, and there are many case reports of severe adverse effects in
patients following acute administration of sodium phosphate tablets (28-40 tablets at 1.5 g
sodium phosphate monobasic and 0.398 g sodium phosphate dibasic each, equivalent to
0.474 g P/tablet; 13.3-19 g P total dose) or two bottles of oral sodium phosphate solution
(92 g sodium phosphate equivalent to 23 g phosphorus) for bowel cleansing prior to surgery or
colonoscopy (Ori et al., 2008; Medoff et al., 2004). A rare syndrome of clinical and pathological
effects known as acute phosphate nephropathy has been described in approximately 30 cases.
This syndrome includes formation of calcium-phosphate depositions in the renal tubules,
interstitial fibrosis, hypertension, and acute tubular degeneration and regeneration. This
condition is irreversible and occurs in people with previously normal renal function as well as
those with recognized risk factors including female gender, older age, hypertension, and renal
failure.
In a study designed to investigate the efficacy of sodium phosphate (NaP) in treating
constipation, 43 individuals (age and gender not provided) consumed 4-8 NaP tablets/day for
28 days (Medoff et al., 2004). Each tablet had 1.5 g NaP from a combination of mono- and
dibasic sodium orthophosphate, equivalent to 0.474 g P/tablet. After 48 hours of treatment, the
dose was increased or decreased to a minimum of 2 or a maximum of 12 tablets/day, yielding
doses of 0.95-5.7 g P per person per day; assuming a 70-kg body weight, this is equivalent to a
dose of 13.5-81 mg P/kg-day. Baseline serum calcium, inorganic phosphorus, and potassium
readings were taken for each individual. The study authors did not consider any changes from
baseline values to be clinically significant or requiring treatment. This study is limited by the
small number of participants, variable dosing, and the lack of in-depth investigation of effects on
kidney and bone.
Carbonated Beverage Consumption Studies
Due to the use of phosphoric acid as an acidifying agent, cola drinks and some brands of
root beer and other popular soft drinks contain phosphorus. Values from common soft drinks
have been determined (Massey and Strang, 1982), and they range from <1 mg P/100 mL for
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7-Up and Ginger Ale to 8.9 mg P/lOO mL for Kool-Aid (lemonade flavor) and
19.7 mg P/100 mL for Coca-Cola. There is no measurable calcium in these drinks
(Mazariegos-Ramos et al., 1995).
Data on 1810 children (ages 12-18 years) collected in a national food intake survey
suggest that soft drinks displace milk and fruit juice in the diets of children and adolescents
(Hamack et al., 1999). A number of case-control and cross-sectional studies have been
conducted to address the potential impact of consumption of carbonated beverages on health.
Some of the studies found correlations between carbonated beverage consumption and the
following:
• changes in calcium economy (decreased serum Ca, increased PTH) in children
(Mazariegos-Ramos et al., 1995) and postmenopausal women
(Guerrero-Romero et al., 1999);
• increased incidence of chronic kidney disease (Saldana et al., 2007);
• increased percentage of urinary stone recurrence (Shuster et al., 1992); and
• increased occurrence of bone fractures among active adolescent girls (Wyshak, 2000;
Wyshak and Frisch, 1994).
While some of the above studies attempted to distinguish between consumption of
beverages acidified with phosphoric acid and those that were not, only two addressed phosphorus
intake in a manner that could inform toxicity value derivation. There were no significant
differences in phosphorus intake between cases and controls in the two studies that quantified
phosphorus intake (i.e., Guerrero-Romero et al., 1999; Mazariegos-Ramos et al., 1995). One
other cross-sectional study found no significant difference in bone mineral density in older
women who consumed carbonated beverages (either one daily serving for >1 year, or more than
one serving daily) compared with those who did not (Kim et al., 1997). In that study, there were
no differences in daily mineral intakes (621-668 mg Ca/day; 1163-1214 mg P/day) between
nonconsumers or occasional consumers and daily or frequent consumers of carbonated
beverages.
While some of the above studies suggest potential impacts of carbonated beverage
consumption on health, there is no clear evidence that any such effect is due to intake of
inorganic phosphate.
Weiner et al. (2001) reported that a handful of human studies have been conducted with
inorganic phosphates. The review of human studies indicated that no adverse effects were
associated with consuming 4-6 g of inorganic phosphate in the form of phosphoric acid (PA) or
monosodium phosphate (MSP) daily for 10 days. The results of these studies provided evidence
that inorganic phosphates exhibit low oral toxicities.
SHORT-TERM, SUBCHRONIC-DURATION, AND CHRONIC-DURATION ANIMAL
STUDIES
Appendix A, Table A. 3 summarizes studies of note that were cited by WHO (1982, 1971,
1965) and IOM (1997), and selected relevant studies published in 1997 or later (after the IOM
publication). Exposure to high concentrations of dietary phosphate has been associated with
increased kidney damage and calcification in dogs, cats, rats, and rabbits (Cockell and Belonje,
2004; Cockell et al., 2002; Matsuzaki et al., 2002, 1999, 1997; Bushinsky et al., 2000;
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DiBartola et al., 1993; Schneider et al., 1981, 1980a,b; MacKay and Oliver, 1935); increased
bone porosity in rabbits (Jowsey and Balasubramaniam, 1972); and increased soft tissue
calcification involving tissues other than kidney in rabbits and guinea pigs (Jowsey and
Balasubramaniam, 1972; House and Hogan, 1955). The observed effects appear to occur
regardless of the form of inorganic phosphate, are greater in females than in males, and, in some
studies, are mitigated by the presence of adequate or increased dietary calcium.
In a 7-year study of wild-caught Cinnamon-tailed monkeys, Anderson et al. (1977) found
no clinical radiographic or histological indicators of bone disease in monkeys fed high-phosphate
diets (1.2% P in the diet equivalent to 600 mg P/kg-day) for 7 years. Bonting and Jansen (1956)
did not observe significant effects on growth, hematology; pathology; or calcium, phosphorus, or
nitrogen balances in three generations of rats fed up to 0.946% dietary phosphorus (equivalent to
a dose of 792 mg P/kg-day); did not observe effects in three generation reproduction of rats
exposed to 1.06% dietary phosphorus (equivalent to a dose of 888 mg P/kg-day). The dietary
composition in this study, which was used by WHO to set an MTDI for phosphorus, was
designed to emulate the calcium and phosphorus composition of a normal Dutch diet. Food and
Drug Research Laboratories, Inc. (1975a,b) did not report any marked developmental effects in
rats and mice fed phosphate in the diet at doses up to 106 and 95 mg P/kg-day, respectively.
Additionally, a toxicological review of inorganic phosphates by Weiner et al. (2001)
including data on the acute, subchronic, and chronic toxicity; genotoxicity; teratogenicity; and
reproductive toxicity from the published literature and from unpublished studies by the
manufacturers is considered for the assessment. Based on toxicity data and similar chemistry,
the inorganic phosphates can be separated into four major classes: monovalent salts, divalent
salts, ammonium salts, and aluminum salts. The classification scheme supports the use of the
oral toxicity data because compounds within a particular class can be used to assess the toxicity
of another compound in the same class (Weiner et al., 2001; WHO, 1982).
Subchronic Toxicity of Inorganic Phosphates
Results from multiple studies in rats, dogs, and sheep ranging from 28 to 100 days
demonstrated that the kidney is a target organ of inorganic phosphate at high doses. At high
phosphate loads, excess phosphate can cause increased bone demineralization and release of
calcium as part of a physiological regulatory mechanism. Excess phosphate and calcium loads
result in nephrocalcinosis and other renal effects. All of the phosphates, with the exception of
SALP (sodium aluminum phosphate), exhibited similar NOAELs. SALP had a NOAEL that was
significantly higher than the NOAELs for other inorganic phosphates—presumably due to the
high contribution of the aluminum ion to the salt's molecular weight and the poor absorption of
the aluminum ion. For the majority of the tested inorganic phosphates, the NOAELs were based
on renal effects. Because the renal effects are due to excess phosphate and calcium loads and not
a direct effect of the cation, Weiner et al. (2001) suggested that all four classes of inorganic
phosphates could produce the same critical effect at high doses. Therefore, a single subchronic
Weiner et al. (2001) stabled NOAELs for all four classes of inorganic phosphates based on the
available data. Based on the lowest subchronic NOAELs observed for three inorganic
phosphates (sodium tripolyphosphate [STP], sodium trimetaphosphate [STMP], and sodium
hexametaphosphate [SHMP]), the group subchronic NOAEL was established at greater than or
equal to 103 mg/kg-day. Appendix A, Table A.4 presents the summary of subchronic-duration
oral toxicity studies of inorganic phosphates reported by Weiner et al. (2001).
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Chronic Toxicity of Inorganic Phosphates
Based on the Weiner et al. (2001) review, results of multiple studies in rats, dogs, and
rabbits ranging from 21 to 104 weeks demonstrated that the kidney is a target organ at high
doses. Excess phosphate loads cause increased bone demineralization and release of calcium as
part of a physiological regulatory mechanism. Excess phosphate and calcium loads result in
nephrocalcinosis and other renal effects. A wide range of chronic NOAELs was established for
inorganic phosphates. The difference between the lowest NOAEL and the highest was over an
order of magnitude. Despite this range, the majority of the NOAELs were based on the same
endpoint (i.e., renal effects). Weiner et al. (2001) reported that, because the renal effects were
due to excess phosphate and calcium loads and not a direct result of the cation, it was expected
that all four classes of inorganic phosphates would produce the same critical effect at high doses.
Therefore, a single chronic NOAEL was established for all four classes of inorganic phosphates
based on the available data. Also, based on the lowest chronic NOAEL observed for two
inorganic phosphates (STP and SHMP), the group chronic NOAEL was established at 0.5%
(257 mg/kg-day). Appendix A, Table A.5 presents a summary of chronic-duration oral toxicity
studies reviewed by Weiner et al. (2001). The two studies used as the basis for the selected
NOAEL of 257 mg/kg-day are summarized below:
STP
In a chronic-duration oral toxicity study, 50 weanling rats (strain not specified) of both
sexes were fed a basal diet of 0 (control group), 0.05, 0.5, or 5.0 % STP (purity not specified),
respectively, for each group in the diet for 104 weeks. Animals in the highest dose group
exhibited retarded growth, increased food consumption, signs of anemia, slightly increased liver
and kidney weights, reduced bone growth, and renal lesions. Histopathological changes in the
kidney consisted of dilated convoluted tubules, hyaline casts, and interstitial fibrosis between the
dilated tubules; fibrotic glomeruli and intertubular calcification occurred in all rats in the highest
dose group. In control rats and those administered 0.05% and 0.5% STP, the kidney changes
were indistinguishable from chronic pyelonephritis of old rats. Mortality was high principally
because of epidemics that occurred at various times. The highest mortality (80%) over the
2-year period was observed in female rats in the highest dose group and the lowest in mortality
(exact percent not reported) in females of 0.05% STP. There was no indication that STP is
carcinogenic. Tumor incidence and type observed were typical of those found in old rats and
were similar in controls and treated animals. The NOAEL for this study was 0.5% in diet, which
is equivalent to 257 mg/kg-day, assuming a 0.35-kg rat consumes 18 g food/day (Weiner et al.,
2001).
SHMP
Rats (strain not specified) (50/sex/group) were administered 0, 0.05, 0.5, or 5.0% SHMP
(purity not specified) in the diet for 2 years. Decreased growth and increased food consumption
were noted in animals fed 5% SHMP. Increased kidney-to-body-weight ratios were noted in the
0.5 and 5%-groups; however, the study authors stated that the organ-weight changes were
difficult to interpret due to a varied incidence of kidney infection. Calcification of the renal
tubules was noted in most rats in the 5%-group and one rat in the 0.5%-group. Hematological
and urine parameters and bone growth were normal in all animals. Tumor incidence and type
were similar in control and treated animals. No effects were noted in the 0.05%-group. Because
the increased kidney-to-body weight ratio in the 0.5%-group was not accompanied by a
significant observation of histopathological renal damage (i.e., only one animal exhibited renal
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calcification), the NOAEL for this study is 0.5% in the diet, equivalent to 257 mg/kg-day,
assuming a 0.35-kg rat consumes 18 g food/day (Weiner et al., 2001).
DEVELOPMENTAL STUDIES
Weiner et al. (2001), in a peer-reviewed journal, summarized results of 18 teratogenic
studies for inorganic phosphates including mono- and divalent ortho- and condensed inorganic
phosphates in pregnant rats, mice, rabbits, and hamsters in different strains. All the
18 teratogenic studies summarized by Weiner et al. (2001) are gavage studies with five dose
levels (including a control) in the range of 0 to 465 mg/kg-day. Weiner et al. (2001) reported
these phosphates lacked teratogenic potential when tested in pregnant rats, mice, rabbits, and
hamsters using standard protocols for teratogenic studies. Based on these results, Weiner et al.
(2001) reported that it was not expected that other inorganic phosphates would be teratogenic.
Similar results are reported by WHO (1982).
In other studies, WHO (1982), in a peer-reviewed document, reported the absence of
maternal or developmental effects after administration of the following phosphates:
(i) monocalcium phosphate (MCP) at dose levels up to 465 mg/kg-day body weight (bw) in mice
and 410 mg/kg bw in rats, (ii) monosodium phosphate (MSP) at dose levels up to 370 mg/kg bw
in mice and 410 mg/kg bw in rats (strain not specified), (iii) sodium acid pyrophosphate (SAPP)
at dose levels up to 355 mg/kg bw in mice, 169 mg/kg bw in rats, 128 mg/kg bw in rabbits, and
166 mg/kg bw in hamsters, (iv) TSPP at dose levels up to 130 mg/kg bw in mice and 138 mg/kg
bw in rats, and (v) SHMP at dose levels up to 370 mg/kg bw in mice, 170 mg/kg bw in rats,
250 mg/kg bw in rabbits, and 141 mg/kg bw in hamsters.
REPRODUCTIVE TOXICITY
Weiner et al. (2001) summarized a two-generation reproductive study with a monovalent
inorganic phosphate (e.g., PA) and one three-generation reproductive study with three condensed
phosphates (e.g., STP, STMP, or SHMP).
As reported by Weiner et al. (2001), an unspecified number of male and female rats
(strain not specified) were administered 0.4 or 0.75% PA (purity not specified) in the diet for
29 weeks. Basel diets contained 1.9% tricalcium phosphate (TCP) (purity not specified) and
0.8%) disodium phosphate (DSP) (purity not specified). After 29 weeks of treatment, the rats
were mated. Eleven weeks after the first mating, the rats were mated again. The study authors
did not indicate whether the parents received a treated diet during the 11 weeks between the first
and second mating. The offspring were maintained on the parental diet for 29 weeks starting at
3 weeks of age. All reproductive parameters, including weight of the mothers, number of living
young, and stillborn per litter, average birth weight of the living young, and number of young left
at weaning, were comparable between controls and treated animals for both generations. There
were no remarkable body-weight changes or gross or histopathological differences between
controls and treated animals. Blood parameters, which were only determined for controls and
the 0.4%-group, were similar between the two groups.
For condensed inorganic phosphates, Hodge (1964) summarized a three-generation
reproductive study, in which 16 female and 8 male rats (strain not specified) per group were
administered and maintained on a diet containing 0, 0.05% STMP (purity not specified),
0.5% STP (purity not specified), or 0.5% SHMP (purity not specified) from weanling to
100 days. Two litters from each generation were examined. Matings were carried out between
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16 females and 8 males of each group when weanling rats were 100 days old. None of the
inorganic phosphates affected fertility, litter size, or growth or survival of the offspring. A slight
increase in kidney weight was observed in rats administered 0.5% STP, but the authors indicated
it was not statistically significant (data not reported). For the third generation, organ weights and
gross and histopathological findings were comparable between controls and treated animals.
These studies were also included in the Weiner et al. (2001) toxicological review of inorganic
phosphates.
Weiner et al. (2001) reported that the study results demonstrated that none of the tested
inorganic phosphates are reproductive toxicants in rats. Also, based on those data, it was not
expected that other inorganic phosphates would be reproductive toxicants. Therefore, it is
suggested that all four classes of inorganic phosphates are grouped together in regards to
reproductive toxicity (Weiner et al., 2001; Hodge, 1964).
DERIVATION OF SUBCHRONIC AND CHRONIC p-RfD
VALUES FOR PHOSPHORUS FROM INORGANIC PHOSPHATES
Phosphorus in the human body is present in both organic and inorganic forms, but its
absorption mostly occurs as inorganic phosphate. Inorganic phosphorus occurs as
orthophosphate (PO43 ), pyrophosphate molecule (P2O74 ), and phosphate linked through an
organic compound (RPO4 ). Inorganic phosphate in extracellular fluids is the measure of
phosphorus intake toxicity. Orthophosphate, as the central unit, is the source of phosphorus
exposure from agricultural and chemical products, and diet. For better clarity, all subsequent
calculations are based on elemental phosphorus, which is contained in inorganic phosphate
(P043 ) (Nordin, 1988; IOM, 1997; Weiner, 2001).
Three starting points (or options) are considered for development of the subchronic and
chronic p-RfDs:
• Optionl: The chronic p-RfD of 1.5 g P/day calculated from animal studies summarized
by Weiner et al. (2001)
• Option 2: The UL of 4.0 g P/day for adults developed by IOM (1997) as the chronic
p-RfD
• Option 3: The subchronic and chronic p-RfD of 3.4 g P/day derived from human study
data reported by Nordin (1988)
The derivation process of the subchronic and chronic p-RfD considered for each option is
described below.
p-RfD CALCULATED FROM WEINER ET AL. (2001)
Option 1: The Chronic p-RfD of 1.5 g P/day Calculated from Animal Studies Summarized
by Weiner et al. (2001)
Based on the chronic-duration toxicity data of various inorganic phosphates summarized
by Weiner et al. (2001) (see Appendix A, Table A.5), the lowest chronic NOAEL was selected as
the POD for deriving a chronic p-RfD. No subchronic p-RfD is developed because the
established subchronic NOAEL of 103 mg/kg-day for inorganic phosphates was considered
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unrealistic and most likely substantially greater than 103 mg/kg-day. This was justified by a
log-fold difference between the NOAEL and LOAEL in the three studies (STP, STMP, and
SHMP) used to determine the group chronic NOAEL. Based on Weiner et al. (2001), the
large-dose spacing was used because these studies were simply preliminary studies used to
establish a dose range for chronic-duration studies with these compounds (Hodge, 1964).
Therefore, the subchronic NOAEL for STP, STMP, and SHMP was most likely considerably
higher than estimated from the preliminary studies. This is supported by the NOAEL established
for the chronic-duration studies on STP, STMP, and SHMP, which are several fold greater than
the NOAEL established in sub chronic-duration studies (Weiner et al., 2001).
Weiner et al. (2001), based on the lowest chronic NOAELs observed for two inorganic
phosphates (i.e., sodium triphosphate [STP] and sodium hexametaphosphate [SHMP]),
established the group chronic NOAEL of 257 mg/kg-day and a LOAEL of 2571 mg/kg-day due
to renal calcification in rats. The assumption for unit conversion by Hodge (1964); Weiner et al.
(2001) included an average body weight of 0.35 kg and a daily food consumption of 18 g/day
and that a rat consuming a diet containing 0.5% of STP or SHMP would ingest 257 mg STP or
SHMP/kg-day (Hodge, 1964; Weiner et al., 2001). Also, the phosphorus atomic weight of
31 g/mol, the STP molecular weight of 368 g/mol, and the SHMP molecular weight of 612 g/mol
were used to express the NOAEL as mass of phosphorus contained in inorganic phosphate (after
accounting for the percentage of P in each compound) as follows:
Adjusted to Daily Average Dose
NOAELadj
The following dosimetric adjustments are made for each dose in the Hodge (1964) study
for diet treatment in adjusting for daily average dose.
Conversion factors: 1% = 10,000 ppm and 1 ppm = 1 mg/kg of food; 0.5% is equivalent
to 5000 mg/kg.
Weiner et al. (2001) used a rat body weight of 0.35 kg, and average daily food
consumption was 18 g/day for both sexes.
NOAELadj (mg/kg-day) =
NOAELadj (mg/kg-day) =
NOAELadj =
NOAELadj =
STP
NOAELHodge, 1964 x [food consumption per day
(kg/day) ^ body weight (kg)] x (days dosed ^ 7 days
per week)
5000 mg/kg x [(0.018 kg/day)] (0.35 kg) x
(7 days dosed ^ 7 days per week)
257.1 mg/kg-day x 1
257.1 mg/kg-day = 0.257 g/kg-day
STP = (0.257 g/kg-day x 93 g/mol + 368 g/mol) = 6.5 x 10 2 g P/kg-day
= 65 mg/kg-day of P contained in a STP mol.
SHMP
SHMP
= (0.257 g/kg-day x 186 g/mol + 612 g/mol = 7.8 x 10
= 78 mg/kg-day of P contained in a SHMP mol.
-2
g P/kg-day
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Among the two proposed NOAELs, the lowest (i.e., 65 mg P/kg-day) is used as the POD to
derive the chronic p-RfD to allow protection of both groups.
p-RfD = POD (NOAEL) - UFC
= (65 mg P/kg-day) ^ 3
= 21.6 mg P/kg-day.
The phosphorus p-RfD of 21.6 mg P/kg-day is equivalent to a human intake of
1512 mg P/day or 1.52 g P/day as illustrated below:
(21.6 mg P/kg-day) x 70 kg human body weight =1512 mg P/day of human intake.
The composite UF (UFc) of 3 is used. Table 1 below summarizes the UFs.
Table 1. Uncertainty Factors for the Chronic p-RfD of Inorganic Phosphates
Using Animal Data Summarized by Weiner et al. (2001)
UF
Value
Justification
UFa
1
A UFa is selected for the following reasons:
1) No significant difference in toxicodynamics of phosphate metabolism between humans
and laboratory animals is expected.
2) Normal blood P, concentration is higher in laboratory animals than in humans, which
represents a toxicokinetic difference. However, this higher concentration results in
greater sensitivity to renal calcification, because the base level of P, is higher. Therefore,
there is no justification to use an UF for animal-to-human extrapolation.
ufd
1
A UFd of 1 is selected because the database includes two acceptable multigeneration
reproduction studies in rats (Bonting and Jansen, 1956; Hodge, 1964) and multiple acceptable
developmental study summaries in rats, mice, rabbits, and hamsters (Weiner et al., 2001), and
there is no indication of other specific endpoint studies that may be relevant.
UFh
3
A UFh of 3 is selected because the analysis was developed based on healthy human adults,
who are more sensitive to phosphate poisoning than children, but the degree of sensitivity is
arguable. The normal plasma levels of phosphate are higher in children than adults, but
toxicity is not observed at these levels, which reduce with age (IOM, 1997; Nordin 1988).
However, adults with kidney impairment and the elderly are more sensitive. The UFH of 3
takes these factors into account.
ufl
1
A UFl of 1 is applied because the POD was developed using a NOAEL.
UFS
1
A UFS of 1 is applied because exposure duration is independent of the critical endpoint (renal
effects) (Hodge, 1964).
UFC
<3000
3
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p-RfD CALCULATED FROM IOM (1997)
Option 2: The UL of 4.0 g P/day for Adults Developed by IOM (1997) as the Chronic p-RfD
IOM (1997) calculated the UL of ~4 g (-130 mmol) P/day for adults by dividing a
NOAEL of 10.2 g P/day by a UF of 2.5. IOM (1997) selected a UF of 2.5 based on the
following rationale:
No benefit is evident from serum inorganic phosphate values above the usual
normal range in adults. Moreover, information is lacking concerning adverse
effects in the zone between normal inorganic phosphate and levels associated
with ectopic mineralization. Therefore, in keeping with the pharmacokinetic
practice where the relationship between intake and blood level is known
(page 187).
UL = NOAEL-UF
= 10.2 g P/day - 2.5
= -4.08 g P/day
The UL of 4.0 is for adults ages 19-70 years old. Assuming a human body weight of 70 kg for
an adult, the UL of 4.0 g P/day is equivalent to 57 mg P/kg-day as illustrated below:
4000 mg P/day - 70 kg = 57 mg P/kg-day.
Appendix A, Table A.6 presents the ULs for different lifestages, as taken from IOM (1997).
p-RfD CALCULATED FROM NORDIN (1988)
Option 3: The Subchronic and Chronic p-RfDs of 3.4 g P/day Derived from Human Study
Data Reported by Nordin (1988).
IOM (1997) estimated a NOAEL of 10.2 g P/day (equivalent to 145.7 mg/kg-day) based
on the upper boundary of adult normal values of serum P* related to the daily phosphorus intake
obtained from an intravenous infusion experiment of neutral phosphate solution at a steadily
increasing rate in adults with normal renal function by Nordin (1988). According to IOM
(1997), the NOAEL of 10.2 g P/day was the highest inorganic phosphate ingested intake in
adults considered normal and the threshold above which elevated inorganic phosphate in the
extracellular fluid (ECF) could result in toxicity.
Figure 2 demonstrates the general relationship between absorbed phosphorus intake and
serum P, in adults, which was derived from Nordin (1988) from a study of neutral phosphate
solution that was intravenously infused at a steadily increasing rate in adults with normal renal
function, thus producing a controlled hyperphosphatemia. Thus, the achieved serum P, is
directly related to the quantity entering the circulation. Serum P* rises rapidly at low intakes
because the filtered load will be below the tubular maximum for phosphate (TmP) and little of
the absorbed phosphorus can be lost in the urine (see Figure 2). The solid curve can be
empirically approximated by the following equation:
P,= 0.00765 x AbsP + 0.8194 x (1 - e*- 0 2635 x AbsP))3 in which P* = serum inorganic
phosphate (in mmol/liter), AbsP = absorbed phosphorus intake (mmol), and 1 mmol phosphorus
= 30.9 mg.
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1.5—1
£ 1.0 —
E
cl"
E
o 0.5 —
,(-0.2635 x AbsP)
Pi= 0.00765 x AbsP + 0.8194 x (1 - e(
P, = serum P, (in mmol/liter),
AbsP = absorbed phosphorus intake (mmol).
Amount Absorbed
o.o
o
10
20
30
40
50
60
70
Amount Ingested
I 1 1 1 1 1 1
0 20 40 60 80 100 120
Phosphorus Intake {irimol/d)
Figure 2. Relation of Serum Inorganic Phosphate to Absorbed Intake in Adults with
Normal Renal Function (IOM, 1997)a
aP, = inorganic phosphate, PO/1 = orthophosphate anion which is the representation of dietary phosphate in 1 mol
(95 g) of inorganic phosphate anion (PO/1 ) that exists as 1 mol (31 g) of inorganic phosphorus (P). 1 mol is equal
to 0.001 mmol and 1 L = 10 dL. From Figure 2, the upper boundary of adult normal values of serum P, is reached
at a daily phosphorus intake of 3.5 g (113 mmol), and the corresponding ingested intake in an adult would be over
10.2 g (330 mmol) P/day.
The steep, ascending portion of the curve, thus, represents a filling up of extracellular
fluid space with absorbed phosphate. At higher intakes, urinary excretion rises to match
absorbed input, and plasma levels change much more slowly. The dashed horizontal lines
represent approximate upper and lower limits of the normal range, while the dashed curves
reflect the relationship between serum P, and ingested intake for absorption efficiencies about
15 percent higher and lower than the average.
According to Figure 2, the upper boundary of adult normal values of serum P, is reached
at a daily phosphorus intake of 3.5 g, the corresponding ingested intake of 10.2 g P/day. This is
the threshold above which elevated ECF serum P, could result in toxicity (Nordin, 1988; IOM,
1997).
No indication has been found that exposure duration (subchronic relative to chronic) to
the same dose level would present different health effects (Weiner et al., 2001), thus, a p-RfD
value of 3.4 g P/day is derived for both subchronic- and chronic-duration exposures from
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inorganic phosphates to human individuals in the age range 1-70 years old and older. Lack of
data precludes derivation of a p-RfD for infants.
Subchronic and Chronic p-RfDs = NOAEL -h UFc
= 10.2 g P/day - 3
= 3.4 g P/day or 48.6 mg P/kg-day.
A UFC of 3 is used. Tables 2 and 3, below, summarize the UFs and the confidence
descriptors.
Table 2. Uncertainty Factors for Subchronic and Chronic p-RfDs of
Inorganic Phosphates Using Human Data"
UF
Value
Justification
UFa
1
A UFa of 1 is applied because a human study is utilized in development of
the POD.
UFd
1
A UFd of 1 is selected because the database includes two acceptable
multigeneration reproduction studies in rats (Bonting and Jansen, 1956;
Hodge, 1964) and multiple acceptable developmental study summaries in
rats, mice, rabbits, and hamsters (Weiner et al., 2001), and there is no
indication of other specific endpoint studies that may be relevant.
UFh
3
A UFh of 3 is selected because the analysis was developed based on healthy
human adults who are more sensitive to phosphate poisoning than children
but the degree of sensitivity is arguable. The normal plasma levels of
phosphate are higher in children than adults, but toxicity is not observed at
these levels, which reduce with age (IOM, 1997; Nordin, 1988). However,
kidney-impaired and elderly adults are more sensitive. The UFh of 3 takes
these factors into account.
UFl
1
A UFl of 1 is applied because the POD was developed using a NOAEL.
UFs
1
A UFs of 1 is applied because the data utilized for derivation of a p-RfD were
independent of exposure duration.
UFC
<3000
3
aIOM (1997) and Nordin (1988).
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The confidence of the subchronic and chronic p-RfDs for phosphorus in inorganic
phosphate is medium, as explained in Table 3 below.
Table 3. Confidence Descriptors for Subchronic and Chronic p-RfDs for Phosphorus in
Inorganic Phosphates
Confidence
Categories
Designation"
Discussion
Confidence in
the study
M
The confidence in the key study is medium. IOM (1997) is a
well-respected scientific review that used data from Nordin
(1988) to estimate the NOAEL. Also, Nordin (1988) used
intravenous infusion experimental data from another
previous study (Bijvoet, 1969, as cited by IOM, 1997). The
relationship between serum P* and absorbed P, intake
established by Nordin (1988) is well supported by results
from other human studies (Heaney and Nordin, 2002) and
animal studies (Weiner et al., 2001).
Confidence in
the database
H
The confidence in the database is high. The database
includes subchronic- and chronic-duration toxicity studies in
more than two species (rats, mice, rabbits, dogs), with
developmental toxicity studies and two multigeneration
reproductive studies.
Confidence in
the p-RfDb
M
The overall confidence in the p-RfD is medium.
aL = Low, M = Medium, H = High.
bThe overall confidence cannot be greater than the lowest entry in the table.
The overall confidence in the p-RfD is medium, given the magnitude of the animal and
human databases, and given the length of time and level of expertise that has gone into IOM's
(2007) analysis and conclusions. Confidence is not high because there are no chronic- or
subchronic-duration human studies that demonstrate a clear dose-response relationship between
phosphorus intake and toxicity.
RATIONALE FOR SELECTION OF THE BEST APPROACH (OPTION 3) FOR
DERIVING SUBCHRONIC AND CHRONIC p-RfDs
The chronic p-RfD of 1.5 g P/day (1.52 mg/kg-day) calculated from animal studies
summarized by Weiner et al. (2001) is the lowest compared to a p-RfD of 3.4 g P/day
(48.6 mg/kg-day) derived using Nordin (1988) human toxicity data, and a UL of 4.0 g P/day
(57 mg/kg-day) for adults established by IOM (1997), but it cannot be considered as the best
option for a subchronic and/or chronic p-RfD because phosphorus density of the diets fed to
laboratory animals is much greater than that of humans, and animals are probably not good
models for determining phosphorus toxicity in humans (IOM, 1997). For example, the median
measured dietary density for phosphorus is 62 mg (2.0 mmol)/100 kcal for human adults
(Cleveland et al., 1996, as cited by IOM, 1997). The corresponding values for rats and mice
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(124-186 mg/100 kcal), cats and dogs (279 mg/100 kcal), and laboratory primates
(155 mg/100 kcal) are much higher.
The definition and steps for deriving a UL (IOM, 1997) and for deriving a p-RfDs
(U.S. EPA, 2002) are similar. However, the application and justification of UFs are notably
different. For both the UL and the p-RfDs, a NOAEL of 10.2 g P/day as a POD has been used
for all ages—except for infants. The UFs applied for the UL ranged from 2.5-3.3 depending on
lifestage (see Appendix A, Table A.6), and a UFc of 3 was applied for deriving RfD. The UFs
for the UL identified the individual contributions of UF components (intrahuman variability,
interspecies variability, subchronic-to-chronic duration, LOAEL-to-NOAEL extrapolation, and
incomplete-to-complete database compensation). These differences between the UL and p-RfD
derivation processes support the exclusion of the UL developed by IOM (1997) as the chronic
p-RfD for phosphorus from inorganic phosphates.
The p-RfD of 3.4 g P/day (48.6 mg/kg-day) derived using a NOAEL of 10.2 g P/day
(145.7 mg/kg-day) as the POD based on elevated ECF serum P, (IOM, 1997; Nordin, 1988) is
considered the best approach to adopt. This option is preferred because of the relevance of
human data to the human health toxicity assessment, a NOAEL obtained from a regression curve
based on data calculations that is inclusive of all the variables that affect inorganic phosphate
absorption, distribution, and excretion, and it shows pharmacokinetic basis of phosphorus intake
in humans. No benchmark dose (BMD) modeling has been performed because the Nordin
(1988) data were unsuitable for BMD modeling (U.S. EPA, 2010).
Based on EPA RfD-derivation methodology (U.S. EPA, 2002), subchronic and chronic
p-RfD values of 3.4 g P/day (48.6 mg P/kg-day) are established. Considering the fact that
phosphorus is an essential nutrient, its p-RfD must take into account both deficiency
(hypophosphatemia) and toxicity (hyperphosphatemia). The IOM (1997) established an RDA,
which is the daily dietary intake level of a nutrient considered sufficient by the Food and
Nutrition Board to meet the requirements of nearly all (97-98%) healthy individuals in each
lifestage and gender group (see Appendix A, Tables A.6 and A.7). The RDA for adults ages
19-70 years old and older is 0.7 g P/day (10 mg P/kg-day). Thus, taken together, the RDA of
10 mg P/kg-day and the p-RfD of 48.6 mg P/kg-day constitute a range of 38.6 mg P/kg-day that
is supportive of human health (i.e., avoids deficiency and protects against toxicity).
DERIVATION OF CHRONIC p-RfC
A chronic RfC of 1 x 10 2 mg/m3 of phosphoric acid is available on the IRIS (U.S. EPA,
2010b) database, and it is based on a sub chronic-duration inhalation toxicity study of rats by
Aranyi et al. (1988). The last update of the assessment was in 1995 (U.S. EPA, 1995). The IRIS
assessment was based on two 13-week inhalation studies of male rats exposed to the combustion
products of 95% red phosphorus and 5% butyl rubber (Aranyi et al., 1988). The critical effect
3 3
was bronchiolar fibrosis with a LOAEL and a NOAEL of 180 mg/m and 50 mg/m ,
respectively. A chronic RfC of 0.01 mg/m3 was derived based on a BMCiohec of 3.4 mg/m3 as
the POD, and a UFc of 300, accounting for a UFa of 3, a UFh of 10, and a UFs of 10. The IRIS
assessment (U.S. EPA, 1995) states that,
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...this RfC is for aerosols ofphosphoric acid and phosphorus oxidation products
and does not apply to elemental phosphorus or other forms ofphosphorus, such
as phosphorus, such as phosphorus salts. Because the site of deposition (and
toxicity) of acid aerosol particulates is dependent on size distribution, and
character, this RfC would be most appropriate for phosphoric acid aerosols in the
range of 0.4-1.0 microns. (Section I.B.5., paragraph 1).
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR INORGANIC PHOSPHATES
WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Three chronic-duration studies reported by Hodge (1964) evaluated the carcinogenicity of
inorganic phosphates in rats after administration via the diet of four dose levels ranging from 0 to
10% of STP (monovalent phosphate), and for SHMP and STMP (condensed phosphates). There
was no indication that the three chemicals (STP, SHMP, STMP) were carcinogenic. The results
indicated that tumor incidence and type were similar in controls to inorganic phosphate-treated
animals. In addition, Hodge (1964) reported no particular concern with regard to genotoxic
activity. Weiner et al. (2001) reached the same conclusion.
In a short-term study of 4 weeks, 5 to 6-week-old male lung cancer model mice
(transgenic) were fed a diet containing 0.5% (normal) inorganic phosphate and 1% inorganic
phosphate (high) (purity not provided) and were tested for effects of high dietary P* on lung
cancer development. Results indicated that high dietary inorganic phosphate activates Akt
signaling and, subsequently, there is a strong correlation with increased lung tumorigenesis
(Jin et al., 2009). These results were consistent with previous studies from the same group that
examined the relationship between high dietary P* intake and lung effects, and Akt signaling
(Xu et al., 2008, 2009; Jin et al., 2007; Chang et al., 2006).
The chronic-duration studies performed by Hodge (1964) did not report information on
lung testing and treatment-related health effects. The short-tem (4 weeks) animal study results
are not sufficient to draw conclusions on the likelihood of inorganic phosphate carcinogenicity.
No additional human or animal data have been located to inform on the potential carcinogenicity
of inorganic phosphate. Thus, under the U.S. EPA (2005) Guidelines for Carcinogen
Assessment, the data are considered to provide "Inadequate Information to Assess Carcinogenic
Potential" for inorganic phosphates. Appendix A, Table A.8 identifies the cancer WOE
descriptor for inorganic phosphates.
QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK
Derivation of quantitative estimates of cancer risk for inorganic phosphate is precluded
by the lack of available data.
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REFERENCES
Anderson, MP; Hunt, RD; Griffiths, HJ; et al. (1977) Long-term effects of low dietary
calcium:phosphate ratio on the skeletons of Cebus albifrons monkeys. JNutr 107(5):834-839.
Aranyi, C; Henry, MC; Vana, SC; et al. (1988) Effects of multiple intermittent inhalation
exposures to red phosphorus/butyl rubber obscurant smokes in Sprague-Dawley rats. Inhal
Toxicol 1:65-78.
ATSDR (Agency for Toxic Substances and Disease Registry). (2009) Toxicological profile
information sheet. Atlanta, GA: U.S. Department of Health and Human Services, Public Health
Service. Available online at http://www.atsdr.cdc.gov/toxprofiles/index.asp.
Bizik, BK; Ding, W; Cerkiewski, FL. (1996) Evidence that bone resorption of young men is not
increased by high dietary phosphorus obtained from milk and cheese. Nutr Res
16(7): 1142-1146.
Bonting, SL; Jansen, BCP. (1956) The effect of a prolonged intake of phosphoric acid and citric
acid in rats. Voeding 17:137-148.
Bushinsky, DA; Parker, WR; Asplin, JR. (2000) Calcium phosphate supersaturation regulates
stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 57(2):550-560.
CalEPA (California Environmental Protection Agency). (2009) Toxicity criteria database.
Office of Environmental Health Hazard Assessment. Available online at
http://www.oehha.ca.gov/risk/ChemicalDB/index.asp. Accessed 9/15/2009.
Calvo, MS; Kumar, R; Heath, H. (1988) Elevated secretion and action of serum parathyroid
hormone in young adults consuming high phosphorus, low calcium diets assembled from
common foods. J Clin EndocrinolMetab 66:823-829.
Calvo, MS; Kumar, R; Heath, H. (1990) Persistently elevated parathyroid hormone secretion
and action in young women after four weeks of ingesting high phosphorus, low calcium diets.
J Clin Endocrinol Metab 70:1334-1340.
Chang, S; Yu, KN; Lee, YS; et al. (2006) Elevated inorganic phosphate stimulates
Akt-ERKl/2-Mnkl signaling in human lung cells. Am JRespir CellMolBiol 35(5):528-539.
Cleveland, LE, Goldman, JD, Borrud, LG. (1996) Data tables: Results from USDA's 1994-96
continuing survey of food intakes by individuals and 1994 diet and health knowledge survey.
Riverdale, MD: Agricultural Research Service, U.S. Department of Agriculture
Cockell, KA; Belonje, B. (2004) Nephrocalcinosis caused by dietary calcium:phosphorus
imbalance in female rats develops rapidly and is irreversible. J Nutr 134(3):637-640.
Cockell, KA; L'Abbe, MR; Belonje, B. (2002) The concentrations and ratio of dietary calcium
and phosphorus influence development of nephrocalcinosis in female rats. J Nutr
132(2):252-256.
24
Inorganic Phosphates
-------
FINAL
3-1-2011
Datta, PK; Frazer, AC; Sharratt, M; et al. (1962) Biological effects of food additives:
II. Sodium pyrophosphate. JSciFoodAgri 13(11):556-566.
DiBartola, SP; Buffington, CA; Chew, DJ; et al. (1993) Development of chronic renal disease
in cats fed a commercial diet. J Am Vet Med Assoc 202(5):744-751.
Dymsza, HA; Reussner, G; Thiessen, R. (1959) Effect of normal and high intakes of
orthophosphate and metaphosphate in rats. JNutr 69:419-428.
Ellinger, RH. (1972) Phosphates in food processing. In: Furia, TE; eds. Handbook of Food
Additives. Vol. I. Cleveland, OH: CRC Press, pp. 617-780.
Fazekas, IG. (1954) Enlargement of parathyroid glands by simple acidic compounds. Vichows
Archiv 324:531-542.
Fettman, MJ; Coble, JM; Hamar, DW; et al. (1992) Effect of dietary phosphoric acid
supplementation on acid-base balance and mineral and bone metabolism in adult cats. Am J Vet
Res 53(11):2125—2135.
Food and Drug Research Laboratories, Inc. (1975a) Teratologic evaluation of FDA 73-65
(monopotassium phosphate) in mice and rats. Unpublished report from Food and Drug Research
Laboratories, Inc., Waverly, NY, USA. Submitted to the U.S. Food and Drug Administration.
Food and Drug Research Laboratories, Inc. (1975b) Teratologic evaluation of FDA 73-2
(monocalcium phosphate; anhydrous) in mice and rats. Unpublished report from Food and Drug
Research Laboratories, Inc., Waverly, NY, USA. Submitted to the U.S. Food and Drug
Administration, Washington, DC.
Grimm, M; Muller, A; Hein, G; et al. (2001) High phosphorus intake only slightly affects
serum minerals, urinary pyridinium crosslinks and renal function in young women. Eur J Clin
Nutr 55(3):153-161.
Guerrero-Romero, F; Rodriguez-Moran, M; Evangelina, R. (1999) Consumption of soft drinks
with phosphoric acid as a risk factor for the development of hypocalcemia in postmenopausal
women. J Clin Epidemiol 52(10): 1007-1010.
Hahn, F. (1961) Toxicology of the polyphosphates. Z Ernahrungsw 1:55-64.
Harnack, L; Stang, J; Story, M. (1999) Soft drink consumption among U.S. children and
adolescents: nutritional consequences. J Am Diet Assoc 99:436-441.
Heaney, RP; Nordin, BEC. (2002) Calcium effects on phosphorus absorption: Implications for
the prevention and co-therapy of osteoporosis. J Am Coll Nutr 21(3):239-244.
Heaney, RP; Recker, RR. (1982) Effects of nitrogen, phosphorus, and caffeine on calcium
balance in women. J Lab Clin Med 99(l):46-55.
Hodge, HC. (1964) Toxicity studies on phosphates. Fd Cosmet Toxicol 2:147-154.
25
Inorganic Phosphates
-------
FINAL
3-1-2011
House, WB; Hogan, AG. (1955) Injury to guinea pigs that follows a high intake of phosphates:
the modifying effect of magnesium and potassium. JNutr 55:507-517.
IARC (International Agency for Research on Cancer). (2009) Monographs on the evaluation of
carcinogenic risks to humans. Lyon, France: IARC. Available online at
http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed 1/15/2010.
IOM (Institute of Medicine). (1997) Dietary Reference Intakes for Calcium, Phosphorus,
Magnesium, Vitamin D, and Fluoride. Food and Nutrition Board, Washington, DC.
Washington, DC: National Academy Press.
JECFA (Joint FAO/WHO Expert Committee on Food Additives). (2009) Summary of
evaluations performed by the Joint FAO/WHO Expert Committee on Food Additives.
Phosphoric acid. Available online at
http://www.inchem.org/documents/jecfa/jeceval/jec_1924.htm. Accessed 1/15/2010.
Jin, H; Chang, SH; Xu, C-X; et al. (2007) High dietary inorganic phosphate affects lung
through altering protein translation, cell cycle, and angiogenesis in developing mice. Toxicol Sci
100 (1):215—223.
Jin, H, Xu, C-X, Lim, H-T et al. (2009) High dietary inorganic phosphate increases lung
tumorigenesis and alters Akt signaling. Am JRespir Crit Care Med 179:59-68.
Jowsey, J; Balasubramaniam, P. (1972) Effect of phosphate supplements on soft-tissue
calcification and bone turnover. Clin Sci 42(3):289-299.
Kemi, VE; Karkkainen, MU; Karp, HJ; et al. (2008) Increased calcium intake does not
completely counteract the effects of increased phosphorus intake on bone: an acute
dose-response study in healthy females. Brit J Nutr 99(4):832-839.
Kemi, VE; Rita, HJ; Karkkainen, MU; et al. (2009) Habitual high phosphorus intakes and foods
with phosphate additives negatively affect serum parathyroid hormone concentration: a
cross-sectional study on healthy premenopausal women. Public Health Nutr 12(10): 1885-1892.
Kim, SH; Morton, DJ; Barrett-Connor, E. (1997) Carbonated beverage consumption and bone
mineral density among older women: the Rancho Bernardo study. Am J Public Health
87(2):276-279.
Lauerson, F. (1953) Zusammenfassende Ubersichtsberichte. Uber gesundheitliche bedenken bei
der verwendung von phosphorsaure und primarem phosphat in erfrischungsgetranken. Libensm
Unters Forsch 96:418-440.
Lewis, JL (2009a) Disorders of phosphate concentration. The Merck Manuals. Online Medical
Library. Available online at http://www.merck.com/mmpe/secl2/chl56/chl56h.html. Accessed
11/19/2010.
Lewis, JL. (2009b) Disorders of calcium concentration. The Merck Manuals. Online Medical
Library. Available online at http://www.merck.com/mmpe/secl2/chl56/chl56g.html. Accessed
11/19/2010.
26
Inorganic Phosphates
-------
FINAL
3-1-2011
MacKay, EM; Oliver, J. (1935) Renal damage following the ingestion of a diet containing an
excess of inorganic phosphate. J Exper Med 61 (3 ): 319-333.
Massey, LK; Strang, MM. (1982) Soft drink consumption, phosphorus intake, and osteoporosis.
J Am Diet Assoc 80(6):581-582.
Matsuzaki, H; Uehara, M; Suzuki, K; et al. (1997) High phosphorus diet rapidly induces
nephrocalcinosis and proximal tubular injury in rats. JNutr Sci Vitaminol 43(6):627-641.
Matsuzaki, H; Kikuchi, T; Kajita, Y; et al. (1999) Comparison of various phosphate salts as the
dietary phosphorus source on nephrocalcinosis and kidney function in rats. JNutr Sci Vitaminol
45(5):595-608.
Matsuzaki, H; Katsumata, S; Masuyama, R; et al. (2002) Sex differences in kidney mineral
concentrations and urinary albumin excretion in rats given high-phosphorus feed. Biosci
BiotechnolBiochem 66(8): 1737-1739.
Mazariegos-Ramos, E; Guerrero-Romero, F; Rodriguez-Moran, M; et al. (1995) Consumption
of soft drinks with phosphoric acid as a risk factor for the development of hypocalcemia in
children: a case-control study. JPediatr 126(6):940-942.
Medoff, J; Katz, S; Malik, P; et al. (2004) Open-label, dose-ranging pilot study of 4 weeks of
low-dose therapy with sodium phosphate tablets in chronically constipated adults. Clin Ther
26(9): 1479-1491.
Nordin, BE. (1988) Phosphorus. J Food Nutr 45:62-75.
NTP (National Toxicology Program). (2005) 11th report on carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Available online at http://ntp-server.mehs.nih.gov/index.cfm?objectid=
32BA9724-F1F6-975E-7FCE50709CB4C932.
NTP (National Toxicology Program). (2009) Management status report. Available online at
http://ntp.niehs.nih.gov/index.cfm?objectid=96A77AlC-123F-7908-7BA79AB04E206892.
Accessed 11/19/2010.
Ori, Y; Herman, M; Tobar, A; et al. (2008) Acute phosphate nephropathy-an emerging threat.
Am J Med Sci 336(4):309-314.
Saldana, TM; Basso, O; Darden, R; et al. (2007) Carbonated beverages and chronic kidney
disease. Epidemiology 18(4):501-506.
Schneider, P; Muller-Peddinghaus, R; Pappritz, G; et al. (1980a) [Potassium hydrogen
phosphate induced nephropathy in the dog. II. Glomerular alterations (author's translation of
abstract)]. Vet Pathol 17(6):720-737.
Schneider, P; Pappritz, G; Muller-Peddinghaus, R; et al. (1980b) [Potassium hydrogen
phosphate induced nephropathy in the dog. I. Pathogenesis of tubular atrophy (author's
translation of abstract)]. Vet Pathol 17(6):699-719.
27
Inorganic Phosphates
-------
FINAL
3-1-2011
Schneider, P; Ober, KM; Ueberberg, H. (1981) Contribution to the phosphate-induced
nephropathy in the dog. Comparative light and electron microscopic investigations on the
proximal tubule after oral application of K2HP04, Na2HP04, KC1 and NaCl. Exp Pathol
19(1):53—65.
Schrodter, K; Bettermann, G; Staffel, T; et al. (1991) Phosphoric acid and phosphates:
4. Toxicology. In: Elvers, B; Hawkins, S; Schulz, G; Eds. Ullmann's encyclopedia of industrial
chemistry, Vol. A19. Federal Republic of Germany: VCH Verlagsgesselschaft, pp. 465, 476,
501-503.
Shuster, J; Jenkins, A; Logan, C; et al. (1992) Soft drink consumption and urinary stone
recurrence: a randomized prevention trial. J Clin Epidemiol 45(8):911-916.
Solutia, Inc. (1972a) 30-day pilot study with levair, kasal and leven-lite in albino rats. Solutia
Study BT710049B.
Solutia, Inc. (1973a) Toxicological investigation of calcium pyrophosphate. Solutia Study
YO730116.
Solutia, Inc. (1973b) Toxicological investigation of diammonium phosphate. Solutia Study
Y0730083, 19 June 1973.
Solutia, Inc. (1973 c) Toxicological investigation of dicalcium phosphate, dihydrate. Solutia
Study Y0730050, 24 April 1973.
Spencer, H; Kramer, I; Otis, D; et al. (1978) Effect of phosphorus on the absorption of calcium
and on the calcium balance in man. JNutr 108(3):447-457.
Stauffer Chemical Company. (1981) A six-month subchronic dietary toxicity study with
Levairl in beagle dogs. Stauffer Chemical Company, Tarpon Springs, FL. Report T-10195.
Stauffer Chemical Company. (1987) 26-week subchronic toxicity study with kasal in dogs.
Stauffer Chemical Company, Tarpon Springs, FL. Report T-12969.
Stauffer Chemical Company. (1986) Four-week dietary comparative toxicity study with kasal in
rats. Stauffer Chemical Company, Tarpon Springs, FL. Report T-12644.
U.S. EPA (Environmental Protection Agency). (1988) Recommendations for and
documentation of biological values for use in risk assessment. Environmental Criteria and
Assessment Office, Cincinnati, OH; EPA/600/6-87/008. Available online at
http://cfpub. epa.gov/ncea/cfm/recordisplay. cfm?deid=34855#Download.
U.S. EPA (Environmental Protection Agency). (1989) Summary review of health effects
associated with elemental and inorganic phosphorus compounds: health issue assessment.
Environmental Criteria and Assessment Office; Office of Health and Environmental Assessment,
Research Triangle Park, NC; EPA/600/8-89/072.
U.S. EPA (Environmental Protection Agency). (1991) Chemical assessments and related
activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
28
Inorganic Phosphates
-------
FINAL
3-1-2011
U.S. EPA (Environmental Protection Agency). (1994) Chemical assessments and related
activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
EPA/600/R-94/904. Available online at
nepi s. epa. gov/Exe/ZyPURL. cgi?Dockey=60001 G8L.txt.
U.S. EPA (Environmental Protection Agency). (1997) Health effects assessment summary
tables (HEAST). FY-1997 update. Prepared by the Office of Research and Development,
National Center for Environmental Assessment, Cincinnati OH for the Office of Emergency and
Remedial Response, Washington, DC; EPA/540/R-97/036. NTIS PB97-921199. Available
online at http://cfpub.epa.gov/ncea/cfm/recordisplay.cfm?deid=2877#Download.
U.S. EPA (Environmental Protection Agency). (2002) Review of the reference dose and
reference concentration process. Final Report. Prepared for the Risk Assessment Forum. Office
of Research and Development, National Center for Environmental Assessment, Washington,
DC; EPA/630/P-02/002F. Available online at http://purl.access.gpo.gov/GPO/LPS44861.
U.S. EPA (Environmental Protection Agency). (2005a) Phosphoric acid (CASRN 7664-38-2).
Integrated Risk Information System (IRIS), Washington, DC. Available online at
http://www.epa.gov/iris/subst/0697.htm. Accessed 11/19/2010.
U.S. EPA (Environmental Protection Agency). (2005b) Guidelines for carcinogen risk
assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register
70(66): 17765-17817. Available online at
http://www.epa.gov/raf/publications/pdfs/CANCER_GUIDELINES_FINAL_3-25-05.PDF.
U.S. EPA (Environmental Protection Agency). (2006) 2006 edition of the drinking water
standards and health advisories. Office of Water, Washington, DC; EPA/822/R-06/013.
Washington, DC. Available online at
http://water.epa.gOv/action/advisories/drinking/upload/2009_04_27_criteria_drinking_dwstandar
ds.pdf. Accessed 11/19/2010.
U.S. EPA (Environmental Protection Agency). (2010a) Integrated Risk Information System
(IRIS). Office of Research and Development, National Center for Environmental Assessment,
Washington, DC. Available online at http://www.epa.gov/iris/. Accessed 11/19/2010.
U.S. EPA (Environmental Protection Agency). (2010b) Benchmark dose modeling software.
Available online at http://www.epa.gov/NCEA/bmds/. Accessed 11/19/2010.
FDA (Food and Drug Administration). (1975) Evaluation of the health aspects of phosphates as
food ingredients. Prepared for FDA by the Life Sciences Research office of the Federation of
American Societies for Experimental Biology, SCOGS Report 32, NTIS PB-262-651.
U.S. FDA (Food and Drug Administration). (1979) Phosphates; proposed affirmation of and
deletion from GRAS status as direct and human food ingredients. Fed Reg
44(244):74845-74857.
Weiner, ML, Salminen, WF, Larson, PR. (2001) Toxicological review of inorganic phosphates.
FdChem Toxicol 39(8):759-786.
29
Inorganic Phosphates
-------
FINAL
3-1-2011
WHO (World Health Organization). (1965) Specifications for identity and purity and
toxicological evaluation of some antimicrobials and antioxidants. WHO/Food Additives/24.65
FAO Nutrition Meetings Report Series No. 3 8 A. Eighth Report of the Joint FAO/WHO Expert
Committee on Food Additives. Geneva: WHO.
WHO (World Health Organization). (1971) Toxicological evaluation of some extraction
solvents and certain other substances. FAO Nutrition Meetings Report Series No. 48A
WHO/Food Additives/70.39. FAO Nutrition Meetings Report Series 1971. Fourteenth report of
the Joint FAO/WHO Expert Committee on Food Additives. Geneva: WHO.
WHO (World Health Organization). (1982) Phosphoric acid and phosphate salts. International
Programme on Chemical Safety, FAO/WHO Expert Committee on Food Additives. Geneva:
WHO. Available online at http://www.inchem.org/documents/jecfa/jecmono/vl7je22.htm.
Accessed 11/19/2010.
Wyshak, G. (2000) Teenaged girls, carbonated beverage consumption, and bone fractures.
Arch Pediatr Adolesc Med 154(6):610-613.
Wyshak, G; Frisch, RE. (1994) Carbonated beverages, dietary calcium, the dietary
calcium/phosphorus ratio, and bone fractures in girls and boys. J Adolesc Health 15 (3 ): 210—215.
Xu, CX, Jin, H, Lim, HT et al. (2008) High dietary inorganic phosphate enhances
cap-dependent protein translation, cell-cycle progression, and angiogenesis in the livers of young
mice. Am J Physiol Gastrointest Liver Physiol 295(4):G654-663.
Xu, CX, Jin, H, Chung, YS et al. (2009) Low dietary inorganic phosphate affects the lung
growth of developing mice. J Vet Sci 10(2): 105-113.
Zemel, MB; Linkswiler, HM. (1981) Calcium metabolism in the young adult male as affected
by level and form of phosphorus intake and level of calcium intake. JNutr 111(2):315-324.
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1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
]
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APPENDIX A. DATA TABLES
Table A.l. List of Inorganic Phosphate Compounds per Categories
Chemical
CASRN
Monovalent salts: hydrogen, sodium, potassium
Orthophosphoric acid (PA)
7664-38-2
Polyphosphoric acid (PPA)
8017-16-1
Monosodium phosphate (MSP)
7558-80-7
Disodium phosphate (DSP)
7558-79-4
Trisodium phosphate (TSP)
7601-54-9
Sodium acid pyrophosphate (SAPP)
7758-16-9
Tetrasodium pyrophosphate (TSPP)
7722-88-5
Sodium tripolyphosphate (STP)
7758-29-4
Sodium trimetaphosphate (STMP)
7785-84-4
Sodium polyphosphate (SPP)
68915-31-1
Sodium hexametaphosphate (SHMP)
10124-56-8
Monopotassium phosphate (MKP)
7778-77-0
Dipotassium phosphate (DKP)
7758-11-4
Tripotassium phosphate (TKP)
7778-53-2
Tetrapotassium pyrophosphate (TKPP)
7320-34-5
Potassium tripolyphosphate (KTP)
13845-36-8
Divalent salts: calcium and magnesium
Monocalcium phosphate (MCP)
7758-23-8
Dicalcium phosphate (DCP)
7757-93-9
Tricalcium phosphate (TCP)
7758-87-4
Calcium pyrophosphate (CPP)
7790-76-3
Monomagnesium phosphate (MMP)
7757-86-0
Dimagnesium phosphate (DMP)
7782-75-4
Trimagnesium phosphate (TMP)
7757-87-1
Ammonium salts
Monoammonium phosphate (MAP)
7722-76-1
Diammonium phosphate (DAP)
7783-28-0
Ammonium polyphosphate (APP)
68333-79-9
31
Inorganic Phosphates
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3-1-2011
Table A.l. List of Inorganic Phosphate Compounds per Categories
Chemical
CASRN
IV
Aluminum salts
27
Monoaluminum phosphate (MALP)
13530-50-2
28
Aluminum metaphosphate (ALMP)
13776-88-0
29
Sodium aluminum phosphate (SALP) (tetrahydrate)
10305-76-7
30
Trialuminum sodium tetra decahydrogenoctaorthophosphate (dihydrate)
15136-87-5
31
Sodium aluminum phosphate (SALP) (anhydrous)
10279-59-1
32
Sodium aluminum phosphate (SALP) (acidic)
7785-88-8
32
Inorganic Phosphates
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Table A.2. Human Studies That Address the Effect of Dietary Phosphate and Calcium
on Calcium Economy and Hormones That Affect Calcium Economy
Zemel and Linkswiler (1981)
Study population
8 male university students (18-24 years of age)
Study protocol
Different combinations of Ca and P were given for four sequential 15-day periods
of exposure; each subject received all dose combinations; diets were controlled
and adequate for all nutrients except calcium, as noted below; each subject was his
own control; Ca balance, hormones, and bone resorption were assessed
P and Ca doses (mg/day)
Low Ca (399), low P (1835) control diet
Low Ca (399), highP (1835) supplemented with polyphosphate
Low Ca (399), high P (1835) supplemented with orthophosphate
High Ca (1194), high P (1835) supplemented with orthophosphate
Critical effects of increased P
Ca absorption was significantly lower with polyphosphate than with
orthophosphate; both forms decreased the fractional renal tubular reabsorption of
calcium, but only the orthophosphate supplement improved Ca balance. Ca
equilibrium was only achieved with the orthophosphate supplement. Increase in
PTH secretion (inferred from urinary cyclic AMP measurement); no effect on
bone resorption (inferred from urinary hydroxyproline)
Critical effects of increased Ca
Diminished the increase in PTH secretion and bone resorption observed with high
P, low Ca
Serum Ca and P levels3
Not specifically reported
Bizik et al. (1996)
Study population
7 male university students (22-31 years)
Study protocol
Dietary Ca and P were manipulated with milk and cheese in two sequential 10-day
dietary periods; each subject was his own control
P and Ca doses (mg/day)
1200 Ca, 800 P from food
1200 Ca, 1600 P from food (nitrogen and calories were controlled)
Critical effects of increased P
Nonsignificant increase in serum PTH; no effects on bone resorption (inferred
from urinary deoxypyridinoline)
Critical effects of increased Ca
Not applicable
Serum Ca and P levels
Within normal ranges for all groups
Kemi et al. (2008)
Study population
12 premenopausal females (21-40 years)
Study protocol
High P in association with low, adequate, or high Ca was given in the diet in three
24-hour study periods; each subject was her own control
P and Ca doses (mg/day)
480, 1080, or 1680 Ca with 1850 P from food
Critical effects of increased P
Not applicable
Critical effects of increased Ca
Significantly decreased serum PTH and bone resorption; no effect on bone
formation
Serum Ca and P levels
No significant changes; within normal ranges for all groups
33
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Table A.2. Human Studies That Address the Effect of Dietary Phosphate and Calcium
on Calcium Economy and Hormones That Affect Calcium Economy
Kemi et al. (2009)
Study population
147 premenopausal females (31-43 years)
Study protocol
Cross-sectional study; fasting blood samples were collected, and each subject kept
a 4-day food record from which dietary intake P was calculated; subjects were
sorted into quartiles based on P intake, and the first and fourth quartiles were
compared
P and Ca doses (mg/day)
961 P for lowest quartile
1956 P for highest quartile; mean dietary Ca was 1056; mean dietary P was 1411
Critical effects of increased P
Decreased mean serum ionized Ca (2.5%) and increased serum PTH (2-fold), even
after total dietary Ca was equalized
Critical effects of increased Ca
Not applicable
Serum Ca and P levels
Ionized Ca was within the normal range for all groups (—1.1—2.3 mmol/L)
Heaney and Nordin (2002)
Study population
Data set 1: 191 Roman Catholic nuns (35-65 years)
Data set 2: Mixed group of 88 women and five men (19-78 years)
Study protocol
Data set 1 was a longitudinal, observational, cohort design. Subjects completed
seven-day diet diaries prior to each admission to the metabolic unit, and controlled
diets were prepared for the eight-day inpatient stay to match the self-selected
intakes of nitrogen, P and Ca of the subjects prior to admission. The diet was
constant throughout the stay, and all excreta were collected and analyzed. Stool
collections were timed and demarcated by the use of a nonabsorbable intake
marker (polyethylene glycol), ingested with each meal. During the inpatient
study, subjects maintained their usual intake of medications, vitamin and mineral
supplements, health food preparations, etc. Each such product was analyzed for
its Ca and P content, and those values were included in the total intake of the
nutrients concerned.
The methods for data set 2 were similar to data set 1 except that each balance
study extended over two weeks, the first week for equilibrium, and the second
week for daily fecal collections. The diets were the same every day during this
two-week period, and the intake marker (polyethylene glycol) was fed from
Day 1.
P and Ca doses (mg/day)
Data set 1: The mean intakes of P and Ca (1101 and 696)
Dataset 2: P intake (-1101 and -50% higher than the data set 1 [1044])
Critical effects of increased P
and interactions with Ca
Ca intake increases without a corresponding increase in P intake, P absorption
falls, and the risk of P insufficiency rises. Intakes with high Ca:P ratios can occur
with use of supplements or food fortificants consisting on nonphosphate calcium
salts. Older patients with osteoporosis treated with current generation bone active
agents should receive at least some of the calcium cotherapy in the form of a
calcium phosphate preparation.
Serum Ca and P levels
Not reported
34
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Table A.2. Human Studies That Address the Effect of Dietary Phosphate and Calcium
on Calcium Economy and Hormones That Affect Calcium Economy
Grimm et al. (2001)
Study population
10 females (20-30 years)
Study protocol
Each subject received the control diet for 4 weeks, followed by 6 weeks of
supplementation with high P and Ca, then 4 weeks on control diet
P and Ca doses (mg/day)
Control diet: 1500 Ca, 1700 P
Supplemental diet: 1995 Ca and 3008 P (supplements were tablets that contained
NaH2P04 and Ca5(P04)30H; administered with orange juice)
Critical effects of increased P
and Ca
Intestinal distress, soft stools, or mild diarrhea in all 10 subjects throughout the
high-phosphorus period. No significant changes in serum PTH or indicators of
bone resorption or renal function
Serum Ca and P levels
No significant changes; within normal ranges for all groups
Calvo et al. (1988)
Study population
8 males, 8 females (18-25 years)
Study protocol
24-hour samples were collected following 8 days on a control diet; 24-hour
samples were collected following a subsequent 8-day period on a low Ca, high P
test diet
P and Ca doses (mg/day)
820 Ca, 930 P in control diet
420 Ca, 1660 P in test diet (controlled for calories, protein, carbohydrates, fat,
sodium, and caffeine)
Critical effects of increased P
and low Ca
Increased serum immunoreactive PTH in men (11%) and women (22%); increased
serum 1,25-dihydroxy vitamin D, urinary cAMP (indicative of PTH) and
hydroxyproline (indicative of bone resorption) only in women; decreased serum
ionized Ca (-2%), and total Ca (-1.9%) only in women
Serum Ca and P levels
Within normal ranges for all groups
Calvo et al. (1990)
Study population
15 females (18-25 years)
Study protocol
Participants were assigned to either a control or experimental protocol (low Ca,
high P) diet. Controls consumed a basal diet for 56 days; subjects assigned to the
experimental protocol consumed the basal diet for 28 days then a low Ca, high P
diet for 28 days
P and Ca doses (mg/day)
Basal diet: 801-823 Ca, 884-934 P
Low Ca, highP diet: 417-481 Ca, 1662-1764 P (controlled for calories, protein,
carbohydrates, fat, sodium, and caffeine)
Critical effects of increased P
and low Ca
Increased urinary P excretion; decreased urinary Ca excretion; decreased serum
ionized Ca and total Ca (<3% lower compared with basal diet); increased serum
intact and immunoreactive PTH (31 and 22%, respectively, compared with the
basal diet); no effect on serum 1,25-dihydroxy vitamin D, 2,5-hydroxy vitamin D,
osteocalcin, or alkaline phosphatase; no effects on glomerular filtration or on
markers for bone resorption
Serum Ca and P levels
Within the normal range for Ca in all groups; high normal for P, all groups
35
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Table A.2. Human Studies That Address the Effect of Dietary Phosphate and Calcium
on Calcium Economy and Hormones That Affect Calcium Economy
Heaney and Recker (1982)
Study population
170 premenopausal Roman Catholic nuns who volunteered as subjects for an
ongoing study of osteoporosis (36-45 years)
Study protocol
Subjects were admitted to the hospital for 5-day examinations as part of the
ongoing study; they received diets constructed to resemble their typical daily
intake of Ca, P, nitrogen, caffeine, and Ca:P ratio. Calcium balance was studied,
and mathematical relationships were estimated from the data through stepwise
multiple linear regression
P and Ca doses (mg/day)
Mean (range): Ca = 0.660 (0.159-2.273); P = 1.145 (0.511-2.453)
Critical effects of increased P
There was no net association of phosphorus intake with calcium balance; higher
phosphorus intake was associated with slightly higher intestinal secretion of
calcium and slightly lower levels of urinary calcium
Serum Ca and P levels
Not reported
Spencer et al. (1978)
Study population
19 males (38-65 years)
Study protocol
Each subject received a basal diet for 22-40 days, then an experimental diet for
28-48 days. Metabolic balances of calcium, phosphorus, and nitrogen were
determined over a 6-day metabolic period. Calcium was varied by adding calcium
gluconate tablets to the basal diet; phosphorus was varied by adding sodium
glycerophosphate to the basal diet; Ca was monitored by [47Ca] tracer
P and Ca doses (mg/day)
Low Ca, control P: 219 Ca, 854 P
Low Ca, highP: 217 Ca, 2008 P
Normal Ca, control P: 828 Ca, 845 P
Normal Ca, highP: 823 Ca, 1977 P
Intermediate Ca, control P: 1433 Ca, 768 P
Intermediate Ca, highP: 1437 Ca, 1964 P
High Ca, control P: 2018 Ca, 805 P
High Ca, highP: 2019 Ca, 1003 P
High Ca, control P: 2745 Ca, 938 P
High Ca, high P: 2757 Ca, 2039 P
Critical effects of increased P
and interactions with Ca
Calcium balance was not significantly affected by any combination. No change in
calcium absorption was observed at any phosphorus concentration. Urinary
calcium decreased significantly with phosphorus intake except during high
calcium intake. Stool calcium significantly increased during phosphorus
supplementation only when calcium was low. Urinary and fecal phosphorus
increased significantly in all studies; phosphorus balance increased significantly
only during high calcium intakes.
Serum Ca and P levels
Based on Table 3 of the study, multiplying percent dose/L plasma x Ca intake in
mg/day yields plasma Ca values in mg/L; dividing by 10 gives Ca values in
mg/DL. Using 8.8-10.4 mg/DL as the range for normal serum Ca levels in adults
(Lewis, 2009b), most of the nine subjects for which values are reported in Table 3
of the study would be considered hypocalcemic regardless of phosphate intake and
level of calcium supplementation.
aNormal range for serum Ca in adults is 8.8-10.4 mg/DL (2.2-2.6 mmol/L); normal range for serum phosphate in
adults is 2.5-4.5 mgP/DL (0.81-1.45 mmol/L) (Lewis, 2009a,b); 30-50% higher values for serum phosphate are
considered normal for young children; ranges can vary between laboratories.
36
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Table A.3. Key Animal Studies Cited by WHO (1982,1971,1965) and IOM (1997),
and Selected New Studies Published Post-1997
Anderson et al. (1977)
Study population
Monkeys, 26 wild Cinnamon-tailed (Cebus albifrons), male and female
Study protocol
Groups were fed a purified diet with Ca:P ratios of 1:4 (Ca deficient, high P04),
1:2.1 (adequate Ca, high P04); 1:0.4 (adequate in both Ca and P04); or a
commercial diet with a 1:0.5 Ca:P ratio for 3-88 months.
P and Ca doses
P concentrations: 1.2, 2.0, 0.4, and 0.47%
Ca concentrations: 0.3, 0.95, 0.95, and 0.86%
Critical endpoints studied
Clinical, radiographic, and histologic indicators of bone disease were monitored
throughout 7 years of study
Critical effects of increased P
None
Critical effects of increased Ca
None
Critical dose(s) as P
NOAEL: 600 mg/kg-day (from 1.2% diet, based on assumptions of 2 kg body
weight and 150 g diet/day, from experimental values presented in the report)
Bonting and Jansen (1956)
Study population
Rat (strain not reported), male and female
Study protocol
Three-generation 90-week study
P and Ca doses (mg/day)
Three successive generations of rats were fed diets containing 0.4 or 0.75%
phosphoric acid for 90 weeks. The basal diet in this study was designed to
emulate the average Dutch diet with 0.62% Ca and 0.82% P (Ca:P = 0.76). Total
dietary P was 0.8, 0.946, and 1.06% in the control and two supplemented diets,
respectively.
Critical endpoints studied
Reproduction, growth, hematology, pathology; Ca, P, and N balances
Critical effects of increased P
None
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NOAEL: 792 mg/kg-day (based on 0.946% P total in diet as the highest
concentration tested for all critical endpoints; standard assumptions for body
weight and food consumption per EPA [1988])
Reproductive NOAEL: 888 mg/kg-day (1.06% total dietary P)
Bushinsky et al. (2000)
Study population
Rat, GHS, female (hypercalciuric strain of Sprague-Dawley)
Study protocol
18-week dietary study of P supplementation/reduction
P and Ca doses (mg/day)
0.225% P (low), 0.395% P (medium), or 0.565% P (high); Ca was constant and
adequate
Critical endpoints studied
Effect of diminishing dietary P on urinary stone formation
Critical effects of increased P
Kidney stone formation
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NOAEL: 361 mg/kg-day (0.395% dietary P); LOAEL: 511 mg/kg-day (0.56%
dietary P); uses EPA (1988) assumptions for body weight and food consumption
37
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Table A.3. Key Animal Studies Cited by WHO (1982,1971,1965) and IOM (1997),
and Selected New Studies Published Post-1997
Cockell et al. (2004)
Study population
Rat, Sprague-Dawley, female weanlings
Study protocol
16-week dietary study; rats fed a control diet, a test diet, or test diet then control
diet for combinations up to 16 weeks.
P and Ca doses (mg/day)
Control diet (5.2 g Ca + 3.7 g P/kg diet; molar ratio = 1.08); test diet
(5.1 g Ca + 5.5 g P/kg diet; molar ratio = 0.72)
Critical endpoints studied
Nephrocalcinosis
Critical effects of increased P
Increased incidence and severity of nephrocalcinosis after as little as 0.5 weeks of
the test diet; changes were not reversible, as switching to control diet had no
effect on incidence and severity compared with 16 weeks on the control diet
Critical effects of increased Ca
Not reported
Critical dose(s) as P
Adverse Effect Level (AEL): 539 mg/kg-day (5.5 g P/kg diet; based on standard
EPA [1988] assumptions for female Sprague-Dawley rats in a
subchronic-duration study)
Cockell et al. (2002)
Study population
Rat, Sprague-Dawley, male and female weanlings
Study protocol
16-week dietary study to determine the effect of increasing Ca and P together in
commonly used standard laboratory diets
P and Ca doses (mg/day)
AIN-93G diet concentrations (5 g Ca + 3 g P/kg diet), with multiples of Ca and P
at the same ratio (1.5x = 7.5 g Ca + 4.5 g P/kg diet, 2.5x = 12.5 g Ca + 7.5 g P/kg
diet, 4.0x = 20.0 g Ca + 12.0 g P/kg diet), or Ca and P at concentrations found in
the standardized AIN-76A diet (5 g Ca + 5 g P/kg diet), for 16 weeks.
Critical endpoints studied
Kidney calcium concentration and nephrocalcinosis
Critical effects of increased P
Incidence and severity of nephrocalcinosis and kidney Ca concentration in female
rats increased with dietary Ca and P but not to levels in female rats fed at the
AIN-76A Ca:P ratio. Male rats showed limited evidence of kidney Ca
accumulation or nephrocalcinosis
Critical effects of increased Ca
Mitigates incidence and severity but not reversibility
Critical dose(s) as P
NO AEL: 294 mg/kg-day (5 g Ca + 3 g P/kg diet); LOAEL: 441 mg/kg-day (4.5 g
P/kg diet: females only; doses based on standard assumptions by EPA [1988] for
female Sprague-Dawley rats in a subchronic-duration study)
Dymsza et al. (1959)
Study population
Rat, Wistar
Study protocol
0.46 or 1.2% P as orthophosphate and metaphosphate in the diet for up to
150 days
P and Ca doses (mg/day)
Critical endpoints studied
Body weight, organ weights, clinical chemistry, hematology, or heart, kidney, or
bone tissue
Critical effects of increased P
None
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NO AEL: 578 mg/kg-day (from 1.2% diet and measured body weight of 0.487 kg
and food consumption of 0.02347 kg/day)
38
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Table A.3. Key Animal Studies Cited by WHO (1982,1971,1965) and IOM (1997),
and Selected New Studies Published Post-1997
DiBartola et al. (1993)
Study population
Cats, adults fed commercial diets since weaning
Study protocol
0.71% phosphorous and 0.89% calcium in the diet (commercial cat food) from
weaning until 2 years
P and Ca doses (mg/day)
Critical endpoints studied
Renal status
Critical effects of increased P
Renal dysfunction and renal lesions
Critical effects of increased Ca
Not reported
Critical dose(s) as P
AEL: 0.71% diet; no controls
Food and Drug Research Laboratories Inc. (1975a)
Study population
Rat, Wistar, pregnant females
Study protocol
Administration of anhydrous monopotassium phosphate (mixed in water) by daily
gavage at doses of 0, 2.82, 13.1, 60.7, or 282 mg/kg-day onGDs (Gestation Days)
6-15, with a 5-day postexposure period prior to caesarean section on GD 20
P and Ca doses (mg/day)
Critical endpoints studied
Developmental toxicity
Critical effects of increased P
None
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NO AEL: 64 mg/kg-day (from 282 mg/kg-day KH2P04)
Food and Drug Research Laboratories Inc. (1975a)
Study population
CD-I mice, pregnant females
Study protocol
Administration of anhydrous monopotassium phosphate (mixed in water) by daily
gavage at doses of 0, 3.2, 14.8, 68.9, or 320 mg/kg-day, with a 2-day
postexposure period prior to caesarean section on GD 20
P and Ca doses (mg/day)
Critical endpoints studied
Developmental toxicity
Critical effects of increased P
None
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NO AEL: 73 mg/kg-day (from 320 mg/kg-day KH2P04)
Food and Drug Research Laboratories Inc. (1975b)
Study population
Rat, Wistar, pregnant females
Study protocol
Administration of anhydrous monosodium phosphate (mixed in water) by daily
gavage at doses of 0, 4.1, 19.0, 88.3, or 410 mg/kg-day on GDs 6-15, with a
5-day postexposure period prior to caesarean section on GD 20
P and Ca doses (mg/day)
Critical endpoints studied
Developmental toxicity
Critical effects of increased P
None
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NO AEL: 106 (from 410 mg/kg-day NaH2P04)
39
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Table A.3. Key Animal Studies Cited by WHO (1982,1971,1965) and IOM (1997),
and Selected New Studies Published Post-1997
Food and Drug Research Laboratories Inc. (1975b)
Study population
CD-I mice, pregnant females
Study protocol
Administration of anhydrous monosodium phosphate (mixed in water) by daily
gavage at doses of 0, 3.7, 17.2, 79.7, or 370 mg/kg-day, with a 2-day
postexposure period prior to caesarean section on GD 20
P and Ca doses (mg/day)
Critical endpoints studied
Developmental toxicity
Critical effects of increased P
None
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NOAEL: 95 (from 370 mg/kg-day NaH2P04)
Fettman et al. (1992)
Study population
Cats, 3 adult
Study protocol
Test diet: 1.7% dietary phosphoric acid (1.25% total dietary P) for 1 year;
Controls: fed naturally occurring acidifying diet without added acidifiers
(1.23% dietary P) for 1 year; Ca was 1.62 (control); 1.66% (test diet)
P and Ca doses (mg/day)
Critical endpoints studied
Mineral, bone, and taurine balances
Critical effects of increased P
None
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NOAEL: 44 mg/kg-day (from 1.25% dietary P based on measured mean body
weight = 4.7 kg and food consumption rate of 16.6 g diet/day)
House and Hogan (1955)
Study population
Guinea pigs, male and female
Study protocol
Groups of animals were fed diets that contained variable amounts of phosphorus,
calcium, magnesium, and potassium for up to 24 months
P and Ca doses
0.70, 1.19,0.72, 1.31, 1.74, and 1.25% P with 0.67, 0.60, 1.14, 1.14, 1.14, and
2.29% Ca, respectively; 0.9% P + 0.9% Ca with variable magnesium and
potassium; 1.7% P + 0.9% Ca with variable potassium and constant magnesium
Critical endpoints studied
Stiffness and calcium deposition in joints
Critical effects of increased P
No apparent difference between groups with increasing P and unchanging Ca
Critical effects of increased Ca
Not specifically addressed
Critical dose(s) as P
Not determined; authors stated: The symptoms were most severe in the groups
that contained 0.9% calcium, 1.75% phosphorus, 0.04% magnesium, and 0.41%
potassium. When the ratios were changed to contain approximately 0.35% of
magnesium and 1.5% of potassium, the damage to the animals was reduced
remarkably
40
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Table A.3. Key Animal Studies Cited by WHO (1982,1971,1965) and IOM (1997),
and Selected New Studies Published Post-1997
Jowsey and Balasubramaniam (1972)
Study population
Rabbits
Study protocol
Groups of animals were fed a control diet for 10 days, given tibial fractures, then
fed an experimental diet for 4 weeks, 8 weeks, or 6 months
P and Ca doses (mg/day)
Control diet for 4-8 weeks: 662 P04, 1125 Ca; experimental diet for 4 or
8 weeks: 2047 P04, 1125 Ca; control diet for 6 months: 83.6 P04, 89.7 Ca;
experimental diet for 6 months: 207.7 P04, 87.7 Ca
Critical endpoints studied
Serum Ca and P04; 83Sr uptake; histology
Critical effects of increased P
Short-term study: increased serum Ca and P04; calcification of kidney and
thoracic aorta (increased Ca, 86Sr uptake, and histological evidence); increased
bone porosity
Long-term study: increased serum Ca but not P04; increased 86Sr uptake or Ca
content in aorta and kidney, but no histological evidence of calcification;
increased bone porosity
Critical effects of increased Ca
Not reported
Critical dose(s) as P
207.7 mg P04/rabbit/day, long-term study; 2047 mg P04/rabbit/dav for 4-8-week
study; based on average measured values
MacKay and Oliver (1935)
Study population
Rat (strain not reported), female
Study protocol
Nine groups of rats were fed a basal diet alone or supplemented with phosphoric
acid or combinations of mono- and dibasic sodium and potassium salts for up to
44 days
P doses
20 (basal diet), 110 (four groups), 155 (three groups), or 200 mEQ total
phosphate/100 g food
Critical endpoints studied
Renal damage
Critical effects of increased P
Permanent renal lesions characterized by necrosis of the convoluted tubules
followed by regeneration and calcification for all high phosphate diets regardless
of the form of phosphate added
Critical effects of increased Ca
Not reported
Critical dose(s) as P
>110 mEQ phosphate/100 g diet
Matsuzaki et al. (1997)
Study population
Rat, Wistar males
Study protocol
Groups of animals were fed normal or high-phosphate diets for 5, 7, 14, and
21 days
P and Ca doses (mg/day)
0.5% P (normal diet) or 1.5% P (high-P diet)
Critical endpoints studied
Nephrocalcinosis
Critical effects of increased P
High-P diet: Nephrocalcinosis in 4/6 rats after 1 day of feeding and in 6/6 rats at
each subsequent evaluation on Days 3, 5, 7, 14, and 21. Severity increased with
duration of feeding. Nephrocalcinosis was not observed in any rats fed the
normal P diet
Critical effects of increased Ca
Not reported
41
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Table A.3. Key Animal Studies Cited by WHO (1982,1971,1965) and IOM (1997),
and Selected New Studies Published Post-1997
Critical dose(s) as P
NOAEL: 461 mg/kg-day (0.5% in diet based on EPA [1988] assumptions for bw
and food consumption for a subchronic-duration study with male Wistar rats)
LOAEL: 1380 mg/kg-day (1.5% in diet based on EPA [1988] assumptions as
above)
Matsuzaki et al. (1999)
Study population
Rat, Wistar males
Study protocol
Groups of animals were fed various diets supplemented with sodium
dihydrogenphosphate (NaH2P04), potassium dihydrogenphosphate (KH2P04), or
polyphosphate salts (sodium tripolyphosphate [Na5P3Oi0] or potassium
tripolyphosphate [K5P3Oi0]), at levels representing a normal phosphorus diet (as
in the previous study) or a high phosphorus diet (as in the previous study) for
21 days
P doses
0.5% P (normal diet) or 1.5% P (high-P diet)
Critical endpoints studied
Nephrocalcinosis and kidney function
Critical effects of increased P
Nephrocalcinosis was observed in all rats fed a high phosphorus diet, but the
degree of nephrocalcinosis was more severe in rats fed Na5P3Oi0 or K5P3Oi0 than
in rats fed NaH2P04 or KH2P04. Creatinine clearance, urinary albumin excretion,
and Y-acctyl-bcta-D-glucosaminidasc activity in urine were increased only in rats
fed the high phosphorus diet with polyphosphate salts but not with monosodium
or potassium salts
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NOAEL: 461 mg/kg-day (0.5% in diet based on EPA [1988] assumptions for bw
and food consumption for a subchronic-duration study with male Wistar rats)
LOAEL: 1380 mg/kg-day (1.5% in diet based on EPA [1988] assumptions as
above)
Matsuzaki et al. (2002)
Study population
Rat, Wistar males and females
Study protocol
Groups of animals were fed diets containing 0.3, 0.6, 0.9, 1.2, or 1.5% P from
KH2P04 for 21 days
P doses
Critical endpoints studied
Gender differences in kidney mineral concentrations and function measured as
urinary albumin excretion
Critical effects of increased P
0.6%: increased kidney weight (females); increased P and Ca in kidney (females),
and increased albumin in urine (males and females); females fed>0.6% dietary P
had higher kidney calcium and P concentrations than comparable males. Females
fed 1.2 or 1.5% P had higher urinary albumin excretion than comparable males
Critical effects of increased Ca
Not reported
Critical dose(s) as P
NOAEL: 308 mg/kg-day(from 0.3% dietary P based on EPA [1988] assumptions
for female Wistar rats in a subchronic-duration study)
LOAEL: 615 mg/kg-day (from 0.6% dietary P based on EPA [1988] assumptions
as above)
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Table A.3. Key Animal Studies Cited by WHO (1982,1971,1965) and IOM (1997),
and Selected New Studies Published Post-1997
Schneider et al. (1981) (based on abstract)
Study population
Dog, Beagle
Study protocol and doses
Groups of dogs were fed equimolar amounts of K2HP04, Na2HP04, KC1, or NaCl
daily by gavage for 9 or 22 weeks. Controls received no treatment (doses were
not reported in abstract)
Critical endpoints studied
Kidney structure assessed by light and electron microscopy
Critical effects of increased P
Nephrocalcinosis with disseminated atrophy of the proximal tubule in dogs
treated with the phosphates, but not in those treated with chlorides
Critical effects of increased Ca
Not reported
Critical dose(s) as P
Cannot tell from the abstract
Schneider et al. (1980a) (based on abstract)
Study population
Dog, Beagle
Study protocol
Dogs were fed 8 g K^HPOykg diet (1.42 g P/kg diet) for up to 38 weeks to study
phosphate-induced kidney nephropathy
Critical endpoints studied
Nephropathy
Critical effects of increased P
Nephropathy with severe tubular atrophy and significant glomerular selective and
unselective proteinuria
Critical effects of increased Ca
Not reported
Critical dose(s) as P
LOAEL: 51-71 mg/kg-day (1.42 g P/kg diet from 8 g K2HP04/kg diet; using
EPA [1988] assumptions for Beagle dogs eating a dry or moist diet)
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Table A.4. Summary of Animal Subchronic Oral Exposures by Weiner et al. (2001)
Inorganic
Phosphate
Species
Duration
(days)
Doses (% in diet or
mg/kg-day)
NOAEL3
LOAEL
Reference13
Monovalent
PA
Sheep
70
0, 35, 105, 211 mg/kg-day
105
-
McMeniman (1973)
MSP
Sheep
70
0, 43, 129, 258 mg/kg-day
258
-
McMeniman (1973)
DSP
Rat®
30
0 and 5%
-
<2571 (only
dose tested)
Hodge(1964)
DSP
Rat
100
0 and 5%
-
<2571 (only
dose tested)
Datta et al. (1962)
SAPP
Rat
100
0, 1.0, 2.5, 5%
-
<514 (lowest
dose tested)
Datta et al. (1962)
STP
Rat
30
0, 0.2, 2.0, 10.0%
90
Hodge (1964)
SAPP
Rat
100
0, 1.0, 2.5, 5%
<514 (lowest
dose tested)
Datta et al. (1962)
STP
Rat
30
0, 0.2, 2.0,10.0%
103
-
Hodge (1964)
STP
Dogd
30
0, 100 mg/kg-day
100
-
Hodge (1964)
STMP
Rat
30
0, 0.2, 2.0, 10.0%
103
-
Hodge(1964)
Dog
30
0, 100 mg/kg-day
100
-
Hodge(1964)
SHMP
Rat
30
0, 0.2, 2.0,10.0%
103
-
Hodge (1964)
Dog
30
0, 100 mg/kg-day
100
-
Hodge (1964)
Aluminum
SALP
Rat
28
0, 0.7, 3.0%
1543
-
Stauffer (1986)
Rat
30
0, 1.0, 3.0, 5.0, 7.0%
1543
-
Solutia (1972a)
Rat
90
0, 1.0, 3.0%
Males: 1543
Females: 1543
Solutia (1973b)
Rat
90
0,0.03,0.1%
514
-
Solutia (1973c)
Dog
90
0, 0.3, 1.0, 3.0%
751
-
Solutia (1972c)
aThe original table differentiated NOELs from NOAELs because a complete description of each study was not
available, and to avoid misunderstanding, a NOAEL term is used to represent both the no-observed-effect level and
the no-observed-adverse effect level.
bThese references were cited by Weiner et al. (2001).
°The NOAELs or LOAELs were extrapolated from the level of compound in the diet assuming a 0.35-kg rat eats
18 g food/day.
dExtrapolated from the level of compound in the diet assuming a 12.7-kg dog eats 318 g food/day.
- Indicates not available/established.
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Table A.5. Summary of Animal Chronic Oral Exposures by Weiner et al. (2001)
Inorganic
Phosphate
Species
Duration
(weeks)
Doses (% in diet or
mg/kg-day)
NOAEL3
LOAEL
Referenceb
PA
Rat®
>52
Up to 0.75%
338
Ellinger (1972)
MSP
Rabbit
22-70
300-700 mg/kg-day
Not determined
Fazekas (1954)
Sodium
orthophosphate
Rat
30
0 and 8.0%
<3600
U.S. FDA (1975)
Sodium
metaphosphate
Rat
30
0 and 8%
<3600
U.S. FDA (1975)
DKP
Dog
38
0, 800 mg/kg-day
<800
DKP
Rat
21
0.87 or 5.1%
2295
Dymsza et al. (1959)
STP
Rat
39
0, 1.1, 1.8, 3.0, 5.0%
495
Hahn (1961)
STP
Rat
104
0, 0.05, 0.5,5.0%
257
Hodge (1964)
SHMP
Rat
21
0, 0.93, 3.5%
1800
Dymsza et al. (1959)
SHMP
Rat
104
0, 0.05, 0.5, 5.0%
257
Hodge (1964)
STMP
Rat
104
0,0.1, 1.0, 10%
514
Hodge(1964)
TSPP & DSP
Rat
39
0, 1.1, 1.8, 3.0, 5.0%
495
Hahn (1961)
Ammonium
DAP
Rabbit
22-70
300-700 mg/kg-day
Not determined
Fazekas (1954)
Aluminum
SALP
Dog
26
0, 0.3, 1.0, 3.0%
NOAEL: 323 Female,
390 Male
Stauffer (1987)
SALP
Dog
27
0, 0.3, 1.0, 3.0%
NOAEL: 1034 Female,
1087 Male
Stauffer (1981)
aThe original table differentiated NOELs from NOAELs, because a complete description of each study was not
available, and to avoid misunderstanding, a NOAEL term is used to represent both the no-observed-effect level and
the no-observed-adverse effect level.
bThese references were cited by Weiner et al. (2001).
°The NOAELs or LOAELs were extrapolated from the level of compound in the diet assuming a 0.35-kg rat eats
18 g food/day.
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Table A.6. Derivation of Tolerable Upper Intake Levels for Different
Lifestages by IOM (1997)
Lifestage
(Years)
UF
UL
(g P/day)a
UL
(mg P/kg-day)
Uncertainty Factor Justification
Infants
0-1
Not
established
Not
established
Not established
There are no data relating to adverse effects of
phosphorus intake for most of the first year of
life. Therefore, it was impossible to establish a
specific UL for infants.
Children
1-8
3.3
3.0
42.9
To account for potentially increased
susceptibility due to smaller body size.
Adolescents
9-18
2.5
4.0
57.1
There is no evidence to suggest increased
susceptibility to adverse effects during
adolescence. Therefore, the same UL specified
for adults is selected for adolescents, 4.0.
Adults
19-70
2.5
4.0
57.1
The relationship between intake and blood level
is known.
Older adults
>70
3.3
3.0
42.9
Because of an increasing prevalence of impaired
renal function after age 70, a larger UF of 3.3
seems prudent.
Pregnancy
14-50
-2.9
3.5
50.0
During pregnancy, absorption efficiency for
phosphorus rises by 15 percent, and, thus, the
UL associated with the upper end of the normal
range will be about 15 percent lower, which is
about 3.5.
Lactation
14-50
2.5
4.0
57.1
During lactation, the phosphorus economy of a
woman does not differ detectably from the
nonlactating state. Hence, the UL for this
physiologic state is not different from the
nonlactating state.
aNOAEL of 10.2 g P/day (145.7 mg P/kg-day) as the threshold of daily phosphorus intake at which no evidence that
a nominal adult individual may experience any untoward effects.
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Table A.7. Lifestage-Based Recommended Dietary Allowance (RDA) Estimated
by the Food and Nutrition Board (IOM, 1997)
Lifestage
Reference Body
Weight (kg)a
RDA
(mg P/day)
(mg P/kg-day)b
Children 1-3 years
13
460
35
Children 4-8 years
22
500
23
Adolescents 9-18 years
50
1250
25
Adults 19-70 years
69
700
10
Adults >70 years
69
700
10
Pregnancy 13-18 years
NA
1250
NA
Pregnancy 19-50 years
NA
700
NA
Lactation 13-18 years
NA
1250
NA
Lactation 19-50 years
NA
700
NA
aFrom the third National Health and Nutrition Examination Survey (NHANES III, 1988-1994) in the United States;
values are mean of male and female reference weights.
bRD A or UL/reference body weight.
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Table A.8. Cancer WOE Descriptor for Inorganic Phosphates
Possible WOE
Descriptor
Designation
Route
of
Entry
Comments
"Carcinogenic to
Humans "
N/A
N/A
No human cancer studies are available.
"Likely to Be
Carcinogenic to
Humans "
N/A
N/A
No strong animal cancer data are available.
"Suggestive Evidence
of Carcinogenic
Potential"
N/A
N/A
No human or animal cancer studies are available.
"Inadequate
Information to Assess
Carcinogenic
Potential"
X
Oral
Chronic-duration studies did not show any differences
related to tumor incidence and type between the control
and treated groups. However, no test and responses
were reported on lung cancer tumorigenesis.
The studies suggest that high dietary P, strongly
activates Akt signaling, and increased lung
tumorigenesis was only in weaning mice for an
exposure duration of 4 weeks. No other studies were
located that support the carcinogenicity.
"Not Likely to Be
Carcinogenic to
Humans "
N/A
N/A
No strong evidence of noncarcinogenicity in humans is
available.
48
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