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Agronomy and Horticulture Department
Agronomy – Faculty Publications
University of Nebraska - Lincoln Year
When Does Nitrate Become a Risk for
Humans?
David S. Powlson
∗
Tom M. Addiscott
†
Nigel Benjamin
‡
Kenneth G. Cassman
∗∗
Theo M. de Kok
††
Hans van Grinsven
‡‡
Jean-Louis L’hirondel
§
Alex A. Avery
¶
Chris Van Kessel
k
∗
Rothamsted Research
†
Rothamsted Research
‡
Derriford Hospital
∗∗
University of Nebraska - Lincoln, kcassman1@unl.edu
††
University Maastricht
‡‡
Netherlands Environmental Assessment Agency
§
Centre Hospitalier Universitaire de Caen
¶
Hudson Institute
k
University of California–Davis
This paper is posted at DigitalCommons@University of Nebraska - Lincoln.
http://digitalcommons.unl.edu/agronomyfacpub/102
291
Is nitrate harmful to humans? Are the current limits for
nitrate concentration in drinking water justifi ed by science?
ere is substantial disagreement among scientists over the
interpretation of evidence on the issue. ere are two main
health issues: the linkage between nitrate and (i) infant
methaemoglobinaemia, also known as blue baby syndrome,
and (ii) cancers of the digestive tract. e evidence for nitrate as
a cause of these serious diseases remains controversial. On one
hand there is evidence that shows there is no clear association
between nitrate in drinking water and the two main health
issues with which it has been linked, and there is even evidence
emerging of a possible benefi t of nitrate in cardiovascular
health. ere is also evidence of nitrate intake giving protection
against infections such as gastroenteritis. Some scientists suggest
that there is suffi cient evidence for increasing the permitted
concentration of nitrate in drinking water without increasing
risks to human health. However, subgroups within a population
may be more susceptible than others to the adverse health
eff ects of nitrate. Moreover, individuals with increased rates of
endogenous formation of carcinogenic N-nitroso compounds
are likely to be susceptible to the development of cancers in
the digestive system. Given the lack of consensus, there is
an urgent need for a comprehensive, independent study to
determine whether the current nitrate limit for drinking water
is scientifi cally justifi ed or whether it could safely be raised.
When Does Nitrate Become a Risk for Humans?
David S. Powlson and Tom M. Addiscott Rothamsted Research
Nigel Benjamin Derriford Hospital
Ken G. Cassman University of Nebraska
Theo M. de Kok University Maastricht
Hans van Grinsven Netherlands Environmental Assessment Agency
Jean-Louis L’hirondel Centre Hospitalier Universitaire de Caen
Alex A. Avery Hudson Institute
Chris van Kessel* University of California–Davis
I nitrate harmful to humans? Are the current limits for nitrate
concentration in drinking water justifi ed by science? ese
questions were addressed at a symposium on “ e Nitrogen
Cycle and Human Health” held at the annual meeting of the Soil
Science Society of America (SSSA). Although they sound like old
questions, it became clear there is still substantial disagreement
among scientists over the interpretation of evidence on the
issue—disagreement that has lasted for more than 50 years.
is article is based on the discussion at the SSSA meeting and
subsequent email exchanges between some of the participants. It
does not present a consensus view because some of the authors
hold strongly divergent views, drawing diff erent conclusions from
the same data. Instead, it is an attempt to summarize, to a wider
audience, some of the main published information and to high-
light current thinking and the points of contention. e article
concludes with some proposals for research and action. Because of
the divergent views among the authors, each author does not nec-
essarily agree with every statement in the article.
Present Regulatory Situation
In many countries there are strict limits on the permissible
concentration of nitrate in drinking water and in many surface
waters. e limit is 50 mg of nitrate L
−1
in the EU and 44 mg
L
−1
in the USA (equivalent to 11.3 and 10 mg of nitrate-N L
−1
,
respectively). ese limits are in accord with WHO recommen-
dations established in 1970 and recently reviewed and recon-
fi rmed (WHO, 2004). e limits were originally set on the basis
of human health considerations, although environmental con-
cerns, such as nutrient enrichment and eutrophication of surface
waters, are now seen as being similarly relevant. It is the health
D.S. Powlson and T.M. Addiscott, Soil Science Dep., Rothamsted Research, Harpenden,
Herts AL5 2JQ, United Kingdom; N. Benjamin, Derriford Hospital, Brest Rd, Derriford,
Plymouth, PL6 5AA, United Kingdom; K.G. Cassman, Dep. of Agronomy and
Horticulture, Univ. of Nebraska, Lincoln, NE, 68583 USA; T.M. de Kok, Dep. of Health
Risk Analysis and Toxicology, University Maastricht, P.O. Box 616, 6200 MD the
Netherlands; H. van Grinsven, Netherlands Environmental Assessment Agency, P.O.
Box 303, 3720 AH Bilthoven, the Netherlands; J.-L. L’hirondel, Service de rhumatologie,
Centre Hospitalier Universitaire de Caen, 14033 Caen Cedex, France; A.A. Avery, Center
for Global Food Issues, Hudson Inst., PO Box 202, Churchville, VA 24421 USA; C. van
Kessel, Dep. of Plant Sciences, Univ. of California, Davis, CA, 95616 USA.
Copyright © 2008 by the American Society of Agronomy, Crop Science
Society of America, and Soil Science Society of America. All rights
reserved. No part of this periodical may be reproduced or transmitted
in any form or by any means, electronic or mechanical, including pho-
tocopying, recording, or any information storage and retrieval system,
without permission in writing from the publisher.
Published in J. Environ. Qual. 37:291–295 (2008).
doi:10.2134/jeq2007.0177
Received 10 Apr. 2007.
*Corresponding author (cvankessel@ucdavis.edu).
© ASA, CSSA, SSSA
677 S. Segoe Rd., Madison, WI 53711 USA
REVIEWS & ANALYSES
292 Journal of Environmental Quality • Volume 37 • March–April 2008
issues that are the main cause of disagreement; the contrasting
views are set out in the following two sections.
Nitrate and Health
ere are two main health issues: the linkage between ni-
trate and (i) infant methaemoglobinaemia, also known as blue
baby syndrome, and (ii) cancers of the digestive tract. e
evidence for nitrate as a cause of these serious diseases remains
controversial and is considered below.
An Over-Stated Problem?
e link between nitrate and the occurrence of methae-
moglobinaemia was based on studies conducted in the 1940s
in the midwest of the USA. In part, these studies related the
incidence of methaemoglobinaemia in babies to nitrate con-
centrations in rural well water used for making up formula
milk replacement. Comly (1945), who fi rst investigated what
he called “well-water methaemoglobinaemia,” found that the
wells that provided water for bottle feeding infants contained
bacteria as well as nitrate. He also noted that “In every one
of the instances in which cyanosis (the clinical symptom of
methaemoglobinaemia) developed in infants, the wells were
situated near barnyards and pit privies.” ere was an absence
of methaemoglobinaemia when formula milk replacements
were made with tap water. Re-evaluation of these original
studies indicate that cases of methaemoglobinaemia always
occurred when wells were contaminated with human or ani-
mal excrement and that the well water contained appreciable
numbers of bacteria and high concentrations of nitrate (Avery,
1999). is strongly suggests that methaemoglobinaemia,
induced by well water, resulted from the presence of bacteria
in the water rather than nitrate per se. A recent interpretation
of these early studies is that gastroenteritis resulting from bac-
teria in the well water stimulated nitric oxide production in
the gut and that this reacted with oxyhaemoglobin in blood,
converting it into methaemoglobin (Addiscott, 2005).
e nearest equivalent to a present-day toxicological test
of nitrate on infants was made by Cornblath and Hartmann
(1948). ese authors administered oral doses of 175 to 700
mg of nitrate per day to infants and older people. None of the
doses to infants caused the proportion of heamoglobin con-
verted to methaemoglobin to exceed 7.5%, strongly suggest-
ing that nitrate alone did not cause methaemoglobinaemia.
Furthermore, Hegesh and Shiloah (1982) reported another
common cause of infant methaemoglobinaemia: an increase
in the endogenous production of nitric oxide due to infec-
tive enteritis. is strongly suggests that many early cases of
infant methaemoglobinaemia attributed at that time to nitrate
in well water were in fact caused by gastroenteritis. Many
scientists now interpret the available data as evidence that the
condition is caused by the presence of bacteria rather than ni-
trate (Addiscott, 2005; L’hirondel and L’hirondel, 2002). e
report of the American Public Health Association (APHA,
1950) formed the main basis of the current recommended
50 mg L
−1
nitrate limit, but even the authors of the report
recognized that it was compromised by unsatisfactory data
and methodological bias. For example, in many cases, samples
of water from wells were only taken for nitrate analysis many
months after the occurrence of infant methaemoglobinaemia.
About 50 epidemiological studies have been made since 1973
testing the link between nitrate and stomach cancer incidence
and mortality in humans, including Forman et al. (1985) and
National Academy of Sciences (1981). e Chief Medical Of-
fi cer in Britain (Acheson, 1985), the Scientifi c Committee for
Food in Europe (European Union, 1995), and the Subcommit-
tee on Nitrate and Nitrite in Drinking Water in the USA (NRC,
1995) all concluded that no convincing link between nitrate and
stomach cancer incidence and mortality had been established.
A study reported by Al-Dabbagh et al. (1986) compared
incidence of cancers between workers in a factory manufac-
turing nitrate fertilizer (and exposed to a high intake of nitrate
through dust) and workers in the locality with comparable
jobs but without the exposure to nitrate. ere was no signifi -
cant diff erence in cancer incidence between the two groups.
Based on the above fi ndings showing no clear association be-
tween nitrate in drinking water and the two main health issues
with which it has been linked, some scientists suggest that there
is now suffi cient evidence for increasing the permitted concen-
tration of nitrate in drinking water without increasing risks to
human health (L’hirondel et al., 2006; Addiscott, 2005).
Space does not permit here to discuss other concerns
expressed about dietary nitrate, such as risk to mother and
fetus, genotoxicity, congenital malfunction, enlarged thryroid
gland, early onset of hypertension, altered neurophysiological
function, and increased incidence of diabetes. For diff ering
views of other possible health concerns, see L’hirondel and
L’hirondel (2002) and Ward et al. (2006).
Nitrate is made in the human body (Green et al., 1981), the
rate of production being infl uenced by factors such as exercise
(Allen et al., 2005). In recent years it has been shown that body
cells produce nitric oxide from the amino acid L-arginine and
that this production is vital to maintain normal blood circula-
tion (Richardson et al., 2002) and protection from infection
(Benjamin, 2000). Nitric oxide is rapidly oxidized to form
nitrate, which is conserved by the kidneys and concentrated in
the saliva. Nitrate can also be chemically reduced to nitric oxide
in the stomach, where it can aid in the destruction of swallowed
pathogens that can cause gastroenteritis.
Evidence is emerging of a possible benefi t of nitrate in cardio-
vascular health. For example, the coronaries of rats provided water
for 18 mo that contained sodium nitrate became thinner and more
dilated that the coronaries of the rats in the control group (Shuval
and Gruener, 1977). Nitrate levels in water showed a negative
correlation coeffi cient with the standardized mortality ratio for
all cardiovascular diseases (Pocock et al., 1980). In healthy young
volunteers, a short-term increase in dietary nitrate reduced diastolic
blood pressure (Larsen et al., 2006). Based on these data, one could
hypothesize that nitrate might also play a role in the cardiovascular
health benefi t of vegetable consumption (many vegetables contain
high concentrations of nitrate) (Lundberg et al., 2004).
Powlson et al.: When Does Nitrate Become a Risk for Humans? 293
The Need for Caution
Although there is little doubt that normal physiological lev-
els of nitric oxide play a functional role in vascular endothelial
function and the defense against infections (Dykhuizen et al.,
1996), chronic exposure to nitric oxide as a result of chronic
infl ammation has also been implicated, though not unequivo-
cally identifi ed, as a critical factor to explain the association
between infl ammation and cancer (Sawa and Oshima, 2006;
Dincer et al., 2007; Kawanishi et al., 2006). Nitric oxide and
NO-synthase are known to be involved in cancer-related events
(angiogenesis, apoptosis, cell cycle, invasion, and metastasis)
and are linked to increased oxidative stress and DNA damage
(Ying and Hofseth, 2007). Rather than nitrate, the presence of
numerous classes of antioxidants is generally accepted as the ex-
planation for the benefi cial health eff ects of vegetable consump-
tion (Nishino et al., 2005; Potter and Steinmetz, 1996).
A recent review of the literature suggests that certain subgroups
within a population may be more susceptible than others to the
adverse health eff ects of nitrate (Ward et al., 2005). Although there
is evidence showing the carcinogenity of N-nitroso compounds
in animals, data obtained from studies that were focused on hu-
mans are not defi nitive, with the exception of the tobacco-specifi c
nitrosamines (Grosse et al., 2006). e formation of N-nitroso
compounds in the stomach has been connected with drinking
water nitrate, and excretion of N-nitroso compounds by humans
has been associated with nitrate intake at the acceptable daily
intake level through drinking water (Vermeer et al., 1998). e
metabolism of nitrate and nitrite, the formation of N-nitroso
compounds, and the development of cancers in the digestive sys-
tem are complex processes mediated by several factors. Individuals
with increased rates of endogenous formation of carcinogenic
N-nitroso compounds are likely to be susceptible. Known factors
altering susceptibility to the development of cancers in the digestive
system are infl ammatory bowel diseases, high red meat consump-
tion, amine-rich diets, smoking, and dietary intake of inhibitors
of endogenous nitrosation (e.g., polyphenols and vitamin C) (de
Kok et al., 2005; De Roos et al., 2003; Vermeer et al., 1998). In
1995, when the Subcommittee on Nitrate and Nitrate in Drinking
Water reported that the evidence to link nitrate to gastric cancer
was rather weak (NRC, 1995), the stomach was still thought to be
the most relevant site for endogenous nitrosation. Previous studies,
such as those reviewed in the NRC (1995) report, which found
no link between nitrate and stomach cancer, concentrated on the
formation of nitrosamines in the stomach. Recent work indicates
that larger amounts of N-nitroso compounds can be formed in the
large intestine (Cross et al., 2003; De Kok et al., 2005).
Some scientists argue that there are plausible explanations for
the apparent contradictive absence of adverse health eff ects of
nitrate from dietary sources (Van Grinsven et al., 2006; Ward et
al., 2006). Individuals with increased rates of endogenous forma-
tion of carcinogenic N-nitroso compounds are more likely to be
at risk, and such susceptible subpopulations should be taken into
account when trying to make a risk-benefi t analysis for the intake
of nitrate. In view of these complex dose-response mechanisms, it
can be argued that it is not surprising that ecological and cohort
studies (e.g., Van Loon et al., 1998) in general do not provide
statistically signifi cant evidence for an association between nitrate
intake and gastric, colon, or rectum cancers. e experimental
design of most of these studies may not have been adequate to
allow for the determination of such a relationship.
Population studies have the problem that factors infl uenc-
ing health tend to be confounded with each other. is neces-
sitates molecular epidemiological studies aimed at improving
methods for assessing exposure in susceptible subgroups. is
approach requires the development of biomarkers that enable
the quantifi cation of individual levels of endogenous nitrosa-
tion and N-nitroso compounds exposure and methods for
accurate quantifi cation of exposure-mediating factors.
Nitrate, Food Security, and the Environment
It is beyond dispute that levels of nitrate and other N-con-
taining species have increased in many parts of the ecosystem
due to increased use of fertilizers and combustion of fossil
fuels. At present, 2 to 3% of the population in USA and the
EU are potentially exposed to public or private drinking water
exceeding the present WHO (and USA and EU) standard for
nitrate in drinking water. e proportion of the exposed pop-
ulation in the emerging and developing economies is probably
larger and increasing (Van Grinsven et al., 2006).
e environmental impacts of reactive N compounds are seri-
ous, and continued research on agricultural systems is essential to
devise management practices that decrease losses and improve the
utilization effi ciency of N throughout the food chain. At the same
time, the central role of N in world agriculture must be considered.
Agriculture without N fertilizer is not an option if the 6.5 billion
people currently in the world and the 9 billion expected by 2050
are to be fed (Cassman et al., 2003). Losses of reactive N com-
pounds to the environment are not restricted to fertilizers: losses
from manures and the residues from legumes can also be large (Ad-
discott, 2005). Research indicates that simply mandating a reduc-
tion in N fertilizer application rates does not automatically reduce
N losses because there is typically a poor relationship between the
amount of N fertilizer applied by farmers and the N uptake ef-
fi ciency by the crops (Cassman et al., 2002; Goulding et al., 2000).
Instead, an integrated systems management approach is needed to
better match the amount and timing of N fertilizer application to
the actual crop N demand in time and space. Such an approach
would lead to decreased losses of reactive N to the environment
without decreasing crop yields. Many of the potential confl icts be-
tween the agricultural need for N and the environmental problems
caused by too much in the wrong place are being studied within
the International Nitrogen Initiative (INI; http://initrogen.org/), a
networking activity sponsored by several international bodies.
e adverse environmental impact of reactive N species (i.e.,
all N-containing molecules other than the relatively inert N
2
gas that comprises 78% of the atmosphere) deserves attention.
Some of these molecules, such as nitrogen oxides, come from
combustion of fossil fuels in automobiles and power plants. Agri-
culture, however, is the dominant source through the cultivation
of N
2
–fi xing crops and the manufacture and use of N fertilizers
(Turner and Rabalais, 2003). Both have increased greatly over the
294 Journal of Environmental Quality • Volume 37 • March–April 2008
last few decades, and the trend is set to continue (Galloway et al.,
2003; 2004). e subsequent N enrichment causes changes to
terrestrial and aquatic ecosystems and to the environmental ser-
vices they provide. Examples include nitrate runoff to rivers caus-
ing excessive growth of algae and associated anoxia in coastal and
estuarine waters (James et al., 2005; Rabalais et al., 2001) and
deposition of N-containing species from the atmosphere causing
acidifi cation of soils and waters and N enrichment to forests and
grassland savannahs (Goulding et al., 1998). All of these impacts
can radically change the diversity and numbers of plant and ani-
mal species in these ecosystems. Other impacts almost certainly
have indirect health eff ects, such as nitrous oxide production,
which contributes to the greenhouse eff ect and the destruction
of the ozone layer, thereby allowing additional UV radiation to
penetrate to ground level with the associated implications for the
prevalence of skin cancers.
Losses of nitrate to drinking water resources are also associated
with leaky sewage systems. Leaky sewage systems need to be im-
proved for general hygiene considerations. is need is especially
important in developing countries and poor rural areas that do
not have well developed sewage and waste disposal infrastructure.
Returning Question
In considering the management of nitrogen in agriculture and
its fate in the wider environment, the debate keeps returning to
the original question: “Is nitrate in drinking water really a threat
to health?” Interpretations of the evidence remain very diff erent
(L’hirondel et al., 2006; Ward et al., 2006). e answer has a signif-
icant economic impact. e current limits established for ground
and surface waters require considerable changes in practice by
water suppliers and farmers in many parts of the world, and these
changes have associated costs. If nitrate in drinking water is not a
hazard to health, could the current limit be relaxed, perhaps to 100
mg L
−1
? e relaxation could be restricted to situations where the
predominant drainage is to groundwater. Such a change would al-
low environmental considerations to take precedence in the case of
surface waters where eutrophication is the main risk, and N limits
could be set to avoid damage to ecosystem structure and func-
tion. Phosphate is often the main factor limiting algal growth and
eutrophication in rivers and freshwater lakes, so a change in the
nitrate limit would focus attention on phosphate and its manage-
ment—correctly so in the view of many environmental scientists
(Sharpley et al., 1994). It is possible that a limitation on phosphate
might lead to even lower nitrate limits in some freshwater aquatic
environments to restore the diversity of submerged plant life
(James et al., 2005). It could be argued that setting diff erent limits,
determined by health or environmental considerations as appropri-
ate, is a logical response to the scientifi c evidence.
Given the criticisms of the scientifi c foundation of present
drinking water standards and the associated cost-benefi ts of
prevention or removal of nitrate in drinking water, we pro-
pose the need to consider the following issues in discussing an
adjustment of the nitrate standards for drinking water:
• Nitrogen intake by humans has increased via
drinking water and eating food such as vegetables.
• ere is circumstantial and often indirect evidence of
the enhanced risk of cancers of the digestive system after
an increase in the concentration of nitrate in drinking
water. ere is an urgent need to synthesize existing data
and understanding, or to carry out additional research if
necessary, to reach clear and widely accepted conclusions
on the magnitude of the risk. is will require greater
collaboration between scientists who hold opposing views
over the interpretation of currently available data. e
possibility that subgroups within the population respond
diff erently requires quantifi cation and critical examination.
• Nitrogen oxides have a functional role in normal
human physiology, but they are also involved in the
induction of oxidative stress and DNA damage. e
challenge is to quantify and evaluate these risks and
benefi ts of nitric oxide exposure in relation to the
intake of nitrate in drinking water. If humans have a
mechanism to combat infectious disease with nitric
oxide, produced from nitrate consumed in drinking
water and food, what are the long-term eff ects of the
nitric oxide benefi ts compared with the potential
negative health eff ects from higher intake of nitrate?
• If the evaluation of potential adverse health eff ects
from chronic exposure to nitrate levels in drinking
water above 50 mg L
−1
demonstrates that these
adverse eff ects can be considered minor compared
with other issues of health loss associated with air
pollution or life style, would the removal of nitrate
from drinking water to meet the current allowable
concentration standards be cost-effi cient relative to
other potential investments in health improvement?
Although science may not provide society with unequivo-
cal conclusions about the relationship between drinking water
nitrate and health over the short term, there are good reasons to
further explore the issue (Ward et al., 2005). Unfortunately, it re-
mains diffi cult to predict the health risks associated with chronic
nitrate consumption from water that exceeds the current WHO
drinking water standard. One complication is the endogenous
production of nitrate, which makes it more diffi cult than previ-
ously realized to relate health to nitrate intake in water or food.
Practical management strategies to overcome ineffi cient
use of nitrogen by crops and to minimize losses of nitrate and
other N-containing compounds to the environment have to
be developed for agricultural systems worldwide.
Given the lack of consensus, there is an urgent need for a
comprehensive, independent study to determine whether the
current nitrate limit for drinking water is scientifi cally justifi ed or
whether it could safely be raised. Meta-analyses are valuable tools
for generating conclusions about specifi c chronic health eff ects
(e.g., stomach cancer, colon cancer, bladder cancer, specifi c repro-
ductive outcomes). Unfortunately, the number of suitable studies
for any particular health eff ect is likely too small to be detected
by meta-analyses (Van Grinsven et al., 2006). Empirical studies
focused on susceptible subgroups, development of biomarkers
for demonstration of endogenous nitrosation, and methods for
Powlson et al.: When Does Nitrate Become a Risk for Humans? 295
accurate quantifi cation of mediating factors may provide part of
the answers. Moreover, there is also a separate need for determin-
ing water quality standards for environmental integrity of aquatic
ecosystems. It is time to end 50 yr of uncertainty and move for-
ward in a timely fashion toward science-based standards.
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