Pesticides In The Diets Of Infants And Children
Pesticides In The Diets Of Infants And Children
Committee on Pesticides in the Diets of Infants and Children
Board on Agriculture
Board on Environmental Studies and Toxicology
National Research Council
National Academy Press
Washington D.C. 1993
Pesticides are used widely in agriculture in the United States. Their
application has improved crop yields and has increased the quantity of fresh
fruits and vegetables in the diet, thereby contributing to improvements in
But pesticides may also cause harm. Some can damage the environment and
accumulate in ecosystems. And depending on dose, some pesticides can cause a
range of adverse effects on human health, including cancer, acute and chronic
injury to the nervous system, lung damage, reproductive dysfunction, and
possibly dysfunction of the endocrine and immune systems.
Diet is an important source of exposure to pesticides. The trace quantities of
pesticides that are present on or in foodstuffs are termed residues. To minimize
exposure of the general population to pesticide residues in food, the U.S.
Government has instituted regulatory controls on pesticide use. These are
intended to limit exposures to residues while ensuring an abundance and
nutritious food supply. The legislative framework for these controls was
established by the Congress through Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA).
Pesticides are defined broadly in this context to include insecticides,
herbicides, and fungicides.
Tolerances constitute the single, most important mechanism by which EPA limits
levels of pesticide residues in foods. A tolerance is defined as the legal limit
of pesticide residue allowed in or on a raw agricultural commodity and, in
appropriate cases, on processed foods. A tolerance must be established for any
pesticide used on any food crop.
Tolerance concentrations are based primarily on the results of field trials
conducted by pesticide manufacturers and are designed to reflect the highest
residue concentrations likely under normal conditions of agricultural use. Their
principal purpose is to ensure compliance with good agricultural practice.
Tolerances are not based primarily on health considerations.
This report addresses the question of whether current regulatory approaches for
controlling pesticide residues in foods adequately protect infants and children.
The exposure of infants and children and their susceptibility to harm from
ingesting pesticide residues may differ from that of adults. The current
regulatory system does not, however, specifically consider infants and children.
It does not examine the wide range of pesticide exposure patterns that appear to
exist within the U.S. population. It looks only at the average exposure of the
entire population. As a consequence, variations in dietary exposure to
pesticides and health risks related to age and to such other factors as
geographic region and ethnicity are not addressed in current regulatory
Concern about the potential vulnerability of infants and children to dietary
pesticides led the U.S. Congress in 1988 to request that the National Academy of
Sciences (NAS) appoint a committee to study this issue through its National
Research Council (NRC). In response, the NRC appointed a Committee on Pesticide
Residues in the Diets of Infants and Children under the joint aegis of the Board
on Agriculture and the Board on Environmental Studies and Toxicology.
The committee was charged with responsibility for examining scientific and
policy issues faced by government agencies, particularly EPA, in regulating
pesticide residues in foods consumed by infants and children. Specifically, the
committee was asked to examine the adequacy of current risk assessment policies
and methods; to assess information on the dietary intakes of infants and
children; to evaluate data on pesticide residues in the food supply; to identify
toxicological issues of greatest concern; and to develop relevant research
priorities. Expertise represented on the committee included toxicology,
epidemiology, biostatistics, food science and nutrition, analytical chemistry,
child growth and developmental, and pediatrics.
The committee was not asked to consider toxicities resulting from exposures to
microorganisms (bacteria and viruses) or from other naturally occurring
potential toxins. It was not asked to weigh the benefits and risks to be derived
from a plentiful and varied food supply against the potential risks resulting
from pesticide exposure. It was not asked to assess the overall safety of the
In this report, the committee considered the development of children from the
beginning of the last trimester of pregnancy (26 weeks) through 18 years of age,
the point when all biological systems have essentially matured.
Age-Related Variation in Susceptibility and Toxicity
A fundamental maxim of pediatric medicine is that children are not "little
adults." Profound differences exist between children and adults. Infants and
children are growing and developing. Their metabolic rates are more rapid than
those of adults. There are differences in their ability to activate, detoxify,
and excrete xenobiotic compounds. All these differences can affect the toxicity
of pesticides in infants and children, and for these reasons the toxicity of
pesticides is frequently different in children and adults. Children may be more
sensitive or less sensitive than adults, depending on the pesticide to which
they are exposed. Moreover, because these processes can change rapidly and can
counteract one another, there is no simple way to predict the kinetics and
sensitivity to chemical compounds in infants and children from data derived
entirely from adult humans or from toxicity testing adult or adolescent animals.
The committee found both quantitative and occasionally qualitative
differences in toxicity of pesticides between children and adults.
Qualitative differences in toxicity are the consequence of exposures during
special windows of vulnerability - brief periods early in development when
exposure to a toxicant can permanently alter the structure or function of an
organ system. Classic examples include chloramphenicol exposure of newborns and
vascular collapse (gray baby syndrome), tetracycline and dysplasia of the dental
enamel, and lead and altered neurologic development.
Quantitative differences in pesticide toxicity between children and adults are
due in part to age-related differences in absorption, metabolism,
detoxification, and excretion of xenobiotic compounds, that is, to differences
in both pharmacokinetics and pharmacodynamic processes. Differences in size,
immaturity of biochemical and physiological functions in major body systems, and
variation in body composition (water, fat, protein and mineral content) all can
influence the extent of toxicity. Because newborns are the group most different
anatomically and physiologically form adults, they may exhibit the most
pronounced quantitative differences in sensitivity to pesticides. The
committee found that quantitative differences in toxicity between children and
adults are usually less than a factor of approsimately 10-fold.
The committee concluded that the mechanism of action of a toxicant - how it
causes harm - is generally similar in most species and across age and
developmental stages within species. For example, if a substance is cytotoxic in
adults, it is usually also cytotoxic in immature animals.
Lack of data on pesticide toxicity in developing organisms was a recurrent
problem encountered by the committee. In particular, little work has been done
to identify effects that develop after a long latent period or to investigate
the effects of pesticide exposure on neurotoxic, immunotoxic, or endocrine
responses in infants and children. The committee therefore had to rely mostly on
incomplete information derived from studies in mature animals and on chemicals
other than pesticides.
The committee reviewed current EPA requirements for toxicity testing by
pesticide manufacturers, as well as testing modifications proposed by the
agency. In general, the committee found that current and past studies conducted
by pesticide manufacturers are designed primarily to assess pesticide toxicity
in sexually mature animals. Only a minority of testing protocols have supported
extrapolation to infant and adolescent animals or the effects of exposure during
early developmental stages and their sequelae in later life.
Age-Related Differences in Exposure
Estimation of the exposures of infants and children to pesticide residues
requires information on (1) dietary composition and (2) residue concentrations
in and on the food and water consumed. The committee found that infants and
children differ both qualitatively and quantitatively from adults in their
exposure to pesticide residues in foods.
Children consume more calories of
food per unit of body weight than do adults. But at the same time, infants and
children consume far fewer types of foods than do adults. Thus, infants and
young children may consume much more of certain foods, especially processed
foods, than do adults. And water consumption, both as drinking water and as a
food component, is very different between children and adults.
The committee concluded that differences in diet and thus in dietary exposure to
pesticide residues account for most of the differences in pesticide-related
health risks that were found to exist between children and adults. Differences
and exposure were generally a more important source of differences in risks than
were age-related differences in toxicologic vulnerability.
Data from various food consumption surveys were made available to the committee.
In analyzing these data, the committee found it necessary to create its own
computer programs to convert foods as consumed into their component raw
agricultural commodities (RAC's). This analytic approach facilitated the use of
data from different sources and permitted evaluations of total exposure to
pesticides in different food commodities. For processed foods, the committee
noted that effects of processing on residue concentrations should be considered,
but that information on these effects is quite limited. Processing may decrease
or increase pesticide residue concentrations. The limited data available suggest
that pesticide residues are generally decreased by processing; however, more
research is needed to define the direction and magnitude of the changes for
specific pesticide-food combinations. The effect of processing is an important
consideration in assessing the dietary exposures of infants and young children,
who consume large quantities of processed foods, such as fruit juices, baby
food, milk, and infant formula.
Although there are several sources of data on pesticide residues in the United
States, the data are of variable quality, and there are wide variations in
sample selection, reflecting criteria developed for different sampling purposes,
and in analytical procedures, reflecting different laboratory capabilities and
different levels of quantification between and within laboratories. These
differences reflect variations in precision and in the accuracy of methods used
and the different approaches to analytical issues, such as variations in limits
of quantification. There also are substantial differences in data reporting.
These differences are due in part to different record-keeping requirements, such
as whether to identify samples with multiple residues, and differences in
statistical treatment of laboratory results below the limit of quantification.
Both government and industry data on residue concentrations in foods reflect the
current regulatory emphasis on average adult consumption patterns. The committee
found that foods eaten by infants and children are underrepresented in surveys
of commodity residues. Many of the available residue data were generated for
targeted compliance purposes by the Food and Drug Administration (FDA) to find
residue concentrations exceeding the legal tolerances established by the EPA
Survey data on consumption of particular foods are conventionally grouped by
broad age categories. The average consumption of a hypothetical "normal" person
is then used to represent the age group. However, in relying solely on the
average as a measure of consumption, important information on the distribution
of consumption patterns is lost. For example, the high levels of consumption
within a particular age group are especially relevant when considering foods
that might contain residues capable of causing acute toxic effects. Also,
geographic, ethnic, and other differences may be overlooked.
To overcome the problems inherent in the current reliance on "average"
exposures, the committee used the technique of statistical convolution (i.e.,
combining various data bases) to merge distributions of food consumption with
distribution of residue concentrations. This approach permits examination of the
full range of pesticides exposures in the U.S. pediatric population. As is
described in the next section, this approach provides an improved basis over the
approach now used for assessing risks for infants and children.
A New Approach to Risk Assessment for Infants and Children
To properly characterize risk to infants and children from pesticide residues in
the diet, information is required on (1) food consumption patterns of infants
and children, (2) concentrations of pesticides residue in foods consumed by
infants and children, and (3) toxic affects of pesticides, especially effects
that may be unique to infants and children. If suitable data on these three
items are available, risk assessment methods based on the technique of
statistical convolution can be used to estimate the likelihood that infants and
children who experience specific exposure patterns may be at risk. To
characterize potential risks to infants and children in this fashion, the
committee utilized data on distributions of pesticide exposure that, in turn,
were based on distributions of food consumption merged with data on the
distribution on the pesticide residue concentration. The committee found that
age-related differences in exposure patterns for 1-5 year-old children were most
accurately illuminated by using 1-year aged groupings of data on children's food
Exposure estimates should be constructed differently depending on whether acute
or chronic effects are of concern. Average daily ingestion of pesticide residues
is an appropriate measure of exposure for assessing the risk of chronic
toxicity. However, actual individual daily ingestion is more appropriate for
assessing acute toxicity. Because chronic toxicity is often related to long-term
average exposure, the average daily dietary exposure to pesticide residues may
be used as the basis for risk assessment when the potential for delayed,
irreversible chronic effects exist. Because acute toxicity is more often
mediated by peak exposures occurring within a short period (e.g., over the
course of a day or even during a single eating occasion), individual daily
intakes are of interest. Examining the distribution of individual daily intakes
within the population of interest reflects day-to-day variation in pesticide
ingestion both for specific individuals and among individuals.
Children may be exposed to multiple pesticides with a common toxic effect, and
estimates of exposure and of risk could therefore be improved by accounting for
these simultaneous exposures. This can be accomplished by assigning toxicity
equivalence factors to each of the compounds having a common mechanism of
action. Total residue exposure is then estimated by multiplying the actual level
of each pesticide residue by its toxicity equivalence factor and summoning the
results. This information may be combined with data on consumption to construct
a distribution of total exposure to all pesticides having a common mechanism of
action. To test this multiple residue methodology, the committee estimated
children's acute health risks resulting from combined exposure to five members
of the organophosphate insecticide family. This was accomplished by combining
actual food consumption data with data on actual pesticide residue levels.
Through this new analytical procedure, the committee estimated that for some
children, total organophosphate exposures may exceed the reference dose.
Furthermore, although the data were weak, the committee estimated that for some
children exposures could be sufficiently high to produce symptoms of acute
organophosphate pesticide poisoning.
Compared to late-in-life exposures, exposures to pesticides early in life can
lead to a greater risk of chronic effects that are expressed only after long
latency periods have elapsed. Such effects include cancer, neurodevelopmental
impairment, and immune dysfunction. The committee developed new risk assessment
methods to examine this issue.
Although some risk assessment methods take into account changes in exposure with
age, these models are not universally applied in practice. The committee
explored the use of newer risk assessment methods that allow for changes in
exposure and susceptibility with age. However, the committee found that
sufficient data are not currently available to permit wide application of these
On the basis of its findings, the committee recommends that certain changes
be made in current regulatory practice. Most importantly, estimates of expected
total exposure to pesticide residues should reflect the unique characteristics
of the diets of infants and children and should account for all nondietary
intake of pesticides.
Estimates of exposure should take into account the
fact that not all crops are treated with pesticides that can be legally applied
to those crops, and they should consider the effects of food processing and
storage. Exposure estimates should recognize that pesticide residues may be
present on more than one food commodity consumed by infants and children and
that more than one pesticide may be present on one food sample. Lastly,
determinations of safe levels of exposure should take into consideration the
physiological factors that can place infants and children at greater risk of
harm than adults.
Tolerances for pesticide residues on commodities are currently established by
the EPA under FIFRA and FFDCA. A tolerance concentration is defined under FFDCA
as the maximum quantity of a pesticide residue allowable on a raw agricultural
commodity (RAC) (FFDCA, Section 408) and in processed food when the pesticide
concentrates during processing (FFDCA Section 409). Tolerance concentrations on
RACs are based on the results of field trials conducted by pesticide
manufacturers and are designed to reflect the highest residue concentrations
likely under normal agricultural practice. More than 8,500 food tolerances for
pesticides are currently listed in the Code of Federal Regulations (CFR).
Approximately 8,350 of these tolerances are for residues on raw commodities
(promulgated under section 408) and about 150 are for residues known to
concentrate in processed foods (promulgated under section 409).
The determination of what might be a safe level of residue exposure is made by
considering the results of toxicological studies of pesticide's effects on
animals and, when data are available, on humans. Both acute and chronic effects,
including cancer, are considered, although acute effects are treated separately.
These data are used to establish human exposure guidelines (i.e. a reference
dose, RfD) against which one can compare the expected exposure. Exposure is a
function of the amount and kind of foods consumed and the amount and identity of
the residues in the foods with the proposed tolerance. The percent of crop
acreage treated is also considered. If the anticipated residues exceed the RID,
then the proposed tolerance is rejected and the manufacturer may recommend a new
Although tolerances establish enforceable legal limits for pesticide residues in
food, they are not based primarily on health considerations, and they do not
provide a good basis for inference about actual exposures of infants and
children to pesticide residues in or on foods.
Tolerances constitute the only tool that EPA has under the law for controlling
pesticide residues in food. To ensure that infants and children are not
exposed to unsafe levels of pesticide residues, the committee recommends that
epa modify its decision making process for setting tolerances so that it is
based more on health considerations than on agricultural practices. These
changes should incorporate the use of improved estimates of exposures and more
relevant toxicology, along with continued consideration of the requirements of
agricultural production. As a result, human health considerations would be more
fully reflected in tolerance levels. Children should be able to eat a healthful
diet containing legal residues without encroaching on safety margins. This goal
should be kept clear.
The committee believes it is essential to develop toxicity testing procedures
that specifically evaluate vulnerability of infants and children. Testing must
be performed during the developmental period in appropriate animal models, and
the adverse effects that may become evident must be monitored over a lifetime.
Of particular importance are tests for neurotoxicity and toxicity to the
developing immune and reproductive systems. Extrapolation of toxicity data from
adult and adolescent laboratory animals to young humans may be inaccurate.
Careful attention to interspecies differences in pharmacokinetics and metabolism
of pesticides and the relative ages at which organ systems mature is essential.
It is also important to enhance understanding of developmental toxicity,
especially in humans, during critical periods of postnatal development including
infancy and puberty.
For toxic effects other than cancer or heritable mutation, uncertainty factors
are widely used to establish guidelines for human exposure on the basis of
animal testing results. This is often done by dividing the no-observed-effect
level (NOEL) found in animal tests by an uncertainty factor of 100 fold. This
factor compromises two separate factors of 10 fold each: one allows for
uncertainty in extrapolating data from animals to humans; the other accommodates
variation within the human population. Although the committee believes that the
latter uncertainty factor generally provides adequate protection for infants and
children, this population subgroup may be uniquely susceptible to chemical
exposure at particularly sensitive stages of development.
At present, to provide added protection during early development, a third
uncertainty factor of 10 is applied to the NOEL to develop the RfD. This third
10 fold factor has been applied by the EPA and FDA whenever toxicity studies and
metabolic/disposition studies have shown fetal developmental effects.
Because there exists specific periods of vulnerability during postnatal
development, the committee recommends that an uncertainty factor up to the 10
fold factor traditionally used by EPA and FDA for fetal developmental toxicity
should also be considered when there is evidence of postnatal developmental
toxicity and when data from toxicity testing relative to children are
incomplete. The committee wishes to emphasize that this is not a new, additional
uncertainty factor, but rather, an extended application of a uncertainty factor
now routinely used by the agencies for a narrower purpose.
In the absence of data to the contrary, there should be a presumption of greater
toxicity to infants and children. To validate this presumption the sensitivity
of mature and immature individuals should be studied systematically to expand
the current limited data base on relative sensitivity.
Food Consumption Data.
The committee recommends that additional data on the food consumption patterns
of inFants and children be collected within narrow age groups. The available
data indicate that infants and children consume much more of certain foods on a
body weight basis than do adults. Because higher exposures can lead to higher
risks, it is important to have accurate data on food consumption patterns for
infants and children. At present, data are derived from relatively small samples
and broad age groupings, making it difficult to draw conclusions about the food
consumption patterns of infants and children. Because the composition of a
child's diet changes dramatically from birth through childhood and adolescence
to maturity, "market basket" food consumption surveys should include adequate
samples of food consumption by children at 1-year intervals up to age 5, by
children between the ages of 5 and 10 years and by children between 11 and 18
years. Food consumption surveys should be conducted periodically to ascertain
changes in consumption patterns over time.
Pesticide Residue Data.
To maximize the utility of pesticide residue data collected by various
laboratories, the committee recommends the use of comparable analytical methods
and standardized reporting procedures and the establishment of a computerized
data base to collate data on pesticide residues generated by different
laboratories. Reports on pesticide residue testing should describe the food
commodity analyzed (whether processed or raw), the analytical methods used, the
compounds for which tests were conducted, quality assurance and control
procedures, and the limit of quantification of the tests. All findings should be
reported, whether or not the residue sought is found.
- In its surveillance of pesticide residues, FDA should increase the frequency of
sampling of the commodities most likely to be consumed by infants and children.
The residue testing program should include all toxic forms of the pesticide, for
example, its metabolites and degradation products.
- Food residue monitoring should target a special "market basket" survey focused
toward the diets of infants and children.
- Pesticide field trials currently conducted by pesticide manufacturers in support
of registration provide data on variation in residue concentrations associated
with different rates and methods of application. Such data should be consulted
to provide a basis for estimating potential maximum residue levels.
- More complete information is needed on the effects of food processing on levels
of pesticides-both the parent compound and its metabolites-in specific
food-chemical combinations potentially present in the diets of infants and
All exposures to pesticides - dietary and nondietary - need to be considered
when evaluating the potential risks to infants and children. Nondietary
environment sources of exposure include air, dirt indoor surfaces, lawns, and
- Estimates of total dietary exposure should be refined to consider intake of
multiple pesticides with a common toxic effect. Converting residues for each
pesticide with a common mechanism of action to toxicity equivalence factors for
one of the compounds would provide one approach to estimating total residue
levels in toxicologically equivalent units.
- Consumption of pesticide residues in water is an important potential route of
exposure. Risk assessment should include estimates of exposure to pesticides in
drinking water and in water as a component of processed foods.
Given adequate data on food consumption and residues, the committee recommends
the use of exposure distributions rather than single point data to characterize
the likelihood of exposure to different concentrations of pesticide residues.
The distribution of average daily exposure of individuals in the population of
interest is most relevant for use in chronic toxicity risk assessment, and the
distribution of individual daily intakes is recommended for evaluating acute
toxicity. Ultimately, the collection of suitable data on the distribution of
exposures to pesticides will permit an assessment of the proportion of the
population that may be at risk.
Although the committee considers the use of exposure distributions to be more
informative than point estimates of typical exposures, the data available to the
committee did not always permit the distribution of exposures to be well
characterized. Existing food consumption surveys generally involve relatively
small numbers of infants and children, and food consumption data are collected
for only a few days for each individual surveyed. Depending on the purpose for
which they were originally collected, residue data may not reflect the actual
distribution of pesticide residues in the food supply. Since residue data are
not developed and reported in a consistent fashion, it is generally not possible
to pool data sets derived form different surveys. Consequently, the committee
recommends that guidelines be developed for consumption and residue data
permitting characterization of distributions of dietary exposure to pesticides.
The committee identified important differences in susceptibility to the toxic
effects of pesticides and exposure to pesticides in the diet with age. For
carcinogenic effects, the committee proposed new methods of cancer risk
assessment designed to take such differences into account. Preliminary analyses
conducted by the committee suggest that consideration of such differences can
lead to lifetime estimates of cancer risk that can be higher or lower than
estimates derived with methods based on constant exposures. However,
underestimation of risk assuming constant exposure was limited to a factor of
about 3- to 5 fold in all cases considered by the committee. Because these
results are based on limited data and specific assumptions about the mechanisms
by which carcinogenic effects are induced, the applicability of these
conclusions under other conditions should be established.
Currently, most long-term laboratory studies of carcinogenesis and other chronic
end points are based on protocols in which the level of exposure is held
constant during the course of the study. To facilitate the application of risk
assessment methods that allow for changes in exposure and susceptibility with
age, it would be desirable to develop bioassay protocols that provide direct
information on the relative contribution of exposures at different ages to
lifetime risks. Although the committee does consider it necessary to develop
special bioassay protocols for mandatory application in the regulation of
pesticides, it would be useful to design special studies to provide information
on the relative effects of exposures at different ages on lifetime cancer other
risks with selected chemical carcinogens.
In addition to pharmacodynamic models for cancer risk assessment, the committee
recommends the development and application of physiologically based
pharmacokinetics models that describe the unique features of infants and
children. For example, differences in relative organ weights with age can be
easily described in physiologic pharmacokinetics models; special compartments
for the developing fetus may also be incorporated. Physiologically based
pharmacokinetics models can be used to predict the dose of the proximate
toxicant reaching target tissues, and may lead to more accurate estimates of
risk. In summary, better data on dietary exposure to pesticide residues
should be combined with improved information on the potentially harmful effects
of pesticides on infants and children. Risk assessment methods that enhance the
ability to estimate the magnitude of these effects should be developed, along
with appropriate toxicological tests for perinatal and childhood toxicity. The
committee's recommendations support the need to improve methods for estimating
exposure and for setting tolerances to safeguard the health of infants and