1
Background and Approach to the Study

PESTICIDES ARE USED widely in agriculture in the United States. When effectively applied, pesticides can kill or control pests, including weeds, insects, fungi, bacteria, and rodents. Chemical pest control has contributed to dramatic increases in yields for most major fruit and vegetable crops. Its use has led to substantial improvements over the past 40 years in the quantity and variety of the U.S. diet and thus in the health of the public (see, for example, Block et al., 1992).

On the negative side, many pesticides are harmful to the environment and are known or suspected to be toxic to humans. They can produce a wide range of adverse effects on human health that include acute neurologic toxicity, chronic neurodevelopmental impairment, cancer, reproductive dysfunction, and possibly dysfunction of the immune and endocrine systems.

The diet is an important source of exposure to pesticides. The trace quantities of pesticides and their breakdown products that are present on or in foodstuffs are termed residues. Residue levels reflect the amount of pesticide applied to a crop, the time that has elapsed since application, and the rate of pesticide dissipation and evaporation. Pesticide residues are widespread in the U.S. diet. They are consumed regularly by most Americans, including infants and children.

To protect the U.S. public against dietary pesticides and their potentially harmful effects, the U.S. Congress has enacted legislation to regulate residue exposures and to ensure that the food supply is safe as well abundant and nutritious. The two principal components of the legislative framework—the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA)—have provided the foundation for a comprehensive regulatory system.



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Pesticides in the Diets of Infants and Children 1 Background and Approach to the Study PESTICIDES ARE USED widely in agriculture in the United States. When effectively applied, pesticides can kill or control pests, including weeds, insects, fungi, bacteria, and rodents. Chemical pest control has contributed to dramatic increases in yields for most major fruit and vegetable crops. Its use has led to substantial improvements over the past 40 years in the quantity and variety of the U.S. diet and thus in the health of the public (see, for example, Block et al., 1992). On the negative side, many pesticides are harmful to the environment and are known or suspected to be toxic to humans. They can produce a wide range of adverse effects on human health that include acute neurologic toxicity, chronic neurodevelopmental impairment, cancer, reproductive dysfunction, and possibly dysfunction of the immune and endocrine systems. The diet is an important source of exposure to pesticides. The trace quantities of pesticides and their breakdown products that are present on or in foodstuffs are termed residues. Residue levels reflect the amount of pesticide applied to a crop, the time that has elapsed since application, and the rate of pesticide dissipation and evaporation. Pesticide residues are widespread in the U.S. diet. They are consumed regularly by most Americans, including infants and children. To protect the U.S. public against dietary pesticides and their potentially harmful effects, the U.S. Congress has enacted legislation to regulate residue exposures and to ensure that the food supply is safe as well abundant and nutritious. The two principal components of the legislative framework—the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and the Federal Food, Drug, and Cosmetic Act (FFDCA)—have provided the foundation for a comprehensive regulatory system.

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Pesticides in the Diets of Infants and Children Concern has arisen in recent years that the current pesticide regulatory system, which is intended to minimize health risk to the general population, may not adequately protect the health of infants and children. The traditional system assesses dietary pesticide risk on the basis of the average exposure of the entire U.S. population. However, it does not consider the range of exposures that exists within the population, nor does it specifically consider exposures of infants and children. The exposure of infants and children and their susceptibility to harm from ingesting pesticide residues may differ considerably from that of adults. Concern about this uncertainty led the U.S. Congress in 1988 to request that the National Academy of Sciences (NAS) appoint a committee to study scientific and policy issues concerning pesticides in the diets of infants and children through its National Research Council (NRC). The committee was specifically charged with examining. what is known about exposures to pesticide residues in the diets of infants and children; the adequacy of current risk assessment methods and policies; and toxicological issues of greatest concern and in greatest need of further research. PESTICIDE USE A pesticide is defined under FIFRA as ''any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any insects, rodents, nematodes, fungi, or weeds, or any other forms of life declared to be pests, and any substance or mixture of substances intended for use as a plant regulator, defoliant, or desiccant." Pesticides have been used by humankind for centuries. Their use was recorded as early as the eighth century BC when the application of fungicides was documented in Homeric poems (Mason, 1928; McCallan, 1967). From the until the present, numerous mixtures have been developed to control fungi, insects, weeds, and other pests. In the 19th century, sulfur compounds were developed as fungicides, and arsenicals were used to control insects attacking fruits and vegetables. Those compounds were highly toxic and consequently were replaced by chlorinated organic pesticides such as DDT and benzenehexachloride (BHC), which were developed during the 1930s and became widely used in the 1950s and 1960s. Chlorinated hydrocarbon insecticides such as DDT, BHC, dieldrin, aldrin, and toxaphene were enthusiastically adopted by farmers who hoped to control previously uncontrolled insects with what were believed to be relatively safe compounds with long environmental persistence. These chemicals were also used widely in the control

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Pesticides in the Diets of Infants and Children of malaria and other insectborne diseases. By 1955, more than 90% of all pest control chemicals used in U.S. agriculture were synthetic organic compounds, and in 1961 DDT was registered for use on 334 crops. Phenoxy herbicides such as 2,4-dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), and ethylenebisdithiocarbamates (EBDCs) and dicarboximide fungicides also gained widespread use during that time. Beginning in the late 1960s, the potential of the chlorinated hydrocarbons for bioaccumulation and long-term toxicity became widely recognized. Also, pest resistance to chlorinated pesticides became increasingly evident and problematic throughout the 1960s, leading many farmers to substitute organophosphates and carbamates for DDT and other chlorinated compounds. Public pressure to end the use of chlorinated pesticides contributed to the creation of the Environmental Protection Agency (EPA) in 1970 and the ultimate administrative revocation in 1972 of the use of DDT on all food sources in the United States. By the end of the 1980s, most food uses of chlorinated compounds were discontinued in this country, although heavy application continues in other nations. Since the late 1960s, a decline has occurred in insecticide use on major commodities such as corn, soybeans, cotton, and wheat. This decrease was primarily the result of pest management programs, which led to an approximately 50% reduction in pesticide application to cotton crops nationwide. Another important factor was the development and widespread adoption of synthetic pyrethroid compounds, which are applied in gram quantities rather than pounds per acre. During this period, fungicide use on peanuts and wheat declined, but because of the continued application of fungicides to fruits and vegetables and the increasing acreage of those crops under cultivation, the overall volume of fungicides used has remained steady. In contrast, the use of herbicides has increased dramatically. In 1955 approximately 3% of all acreage planted with corn and soybean crops were treated with a herbicide; by 1985 that figure had increased to more than 95%, primarily because of the development of effective herbicides that were applied before the crop was planted. Herbicides now account for approximately 66% of all agricultural pesticides, but for a lower percentage of dietary exposure than is attributed to fungicides and insecticides, which are applied directly to the food closer to, or even after, its harvest. More than 90% of all herbicides are applied to just four crops: corn, soybeans, cotton, and wheat. Today, most pesticides are synthetically produced organic and inorganic chemicals or microbial agents. Some of these pesticides have been found naturally and have been synthetically reproduced for commercial use. The variety and amounts of pesticides now used are far greater than

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Pesticides in the Diets of Infants and Children at any previous time in human history. Approximately 600 pesticides are currently registered with the EPA (P. Fenner-Crisp, EPA, personal commun., 1993). The most common food-use pesticides fall into three classes: insecticides, herbicides, and fungicides. In 1991, an estimated 817 million pounds of active pesticide ingredients were used for agricultural application in the United States. Of this total, herbicides accounted for 495 million pounds; insecticides, 175 million pounds, fungicides, 75 million pounds; and other pesticides, 72 million pounds; (EPA, 1992). "Other" pesticides were defined as rodenticides, fumigants, and molluscicides but do not include wood preservatives, disinfectants, and sulfur. Insecticides. Insecticides control insects that damage crops through a variety of modes. Some work as nerve poisons, muscle poisons, desiccants, sterilants, or pheromones; others exert their effects by physical means such as by clogging air passages. The classes of insecticides most commonly used today are chlorinated hydrocarbons, organophosphates, and carbamates, and of these, the organophosphates are the most widely used. Typically they are very acutely toxic, but they do not persist in the environment. Well-known organophosphate pesticides include parathion, dichlorvos, malathion, chlorpyrifos, and azinphos-methyl. The toxicity to humans resulting from exposure to these compounds can differ markedly from chemical to chemical. The carbamate insecticides are also very widely used  in the United States today. They too are highly toxic, e.g., aldicarb. Other insecticides such as synthetic pyrethroids, e.g., permethrin, are valued because of their fast action and relatively low toxicity to mammals. Herbicides. Herbicides are used to control weeds, which compete with crop plants for water, nutrients, space and sunlight. By reducing the weed population, the need for farm labor is decreased and crop quality is enhanced. Herbicides work through a variety of modes of action. Some damage leaf cells and desiccate the plant; others alter nutrient uptake or photosynthesis. Some herbicides inhibit seed germination or seedling growth. Others are applied to foliage and kill on contact, thereby destroying leaf and stem tissues. Some of the most widely used herbicides are 2,4-D [(2,4-dichlorophenoxy) acetic acid], atrazine, simazine, dacthal, alachlor, metolachlor, and glyphosate. Fungicides. Fungicides control plant molds and other diseases. They include compounds of metals and sulfur as well as numerous synthetics. Some fungicides act by inhibiting the metabolic processes of fungal organisms and can be used on plants that have already been invaded and

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Pesticides in the Diets of Infants and Children damaged by the organism. Other fungicides protect plants from fungal infections and retard fungal growth before damage to plants can occur. Fungicides frequently provide direct benefit to humans by retarding or eliminating fungal infections that can produce toxicants such as aflatoxins. Fungicides that have been used heavily over the years include benomyl, captan, and the EBDC family of fungicides such as mancozeb. In addition to their agricultural applications, pesticides are also used for many nonagricultural purposes, e.g., in homes and public buildings to kill termites and other pests; on lawns and ornamental plantings to kill weeds, insects, and fungi; and on ponds, lakes, and rivers to control insects and weeds. Therefore, humans are exposed to pesticides from a variety of sources other than the diet, for example, through the skin or by inhalation. Some of these exposures are especially important when considering total exposures of infants and children. PESTICIDE CONTROL LEGISLATION The societal response to the dual nature of pesticides—to their combination of benefits and toxicity—has been to develop a comprehensive regulatory system that seeks to make possible the beneficial use of pesticides while minimizing their hazards to public health and the environment. This regulatory system originated with the enactment of FIFRA in 1947. The legislation regulating pesticides in the United States now consists of FIFRA, its comprehensive amendments of 1972, 1975, 1978, 1980, and 1988, and certain provisions of the FFDCA, which was enacted in 1954 and later amended. FIFRA is intended by Congress to be a "balancing" or risk-benefit statute. It states that a pesticide when used for its intended purpose must not cause "unreasonable adverse effects on the environment." This balancing process must take into account "the economic, social, and environmental costs as well as the potential benefits of the use of any pesticide" [7 USC 136(a) (1978)]. Wilkinson (1990, p. 11) has commented: ''While use of the term 'unreasonable risk' implies that some risks will be tolerated  under FIFRA, it is clearly expected that the anticipated benefits will outweigh the potential risks when the pesticide is used according to commonly recognized, good agricultural practices." Under FIFRA, pesticide use is controlled through a registration process. This process is administered by EPA. A given pesticide may have several different uses, and each use is required to have its own registration. EPA registration of a pesticide use and approval of a label detailing the legally binding instructions for that use are required before a pesticide can be legally sold.

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Pesticides in the Diets of Infants and Children For a pesticide to be registered, manufacturers must submit to EPA the data needed to support the product's registration, including substantiation of its usefulness and disclosure of its chemical and toxic properties, its likely distribution in the environment, and its possible effects on wildlife and plants. Pesticides that are to be registered for use on food crops must be granted a tolerance by EPA. These tolerances constitute the principal mechanism by which EPA limits levels of pesticides residues in foods. 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 has concentrated during processing (FFDCA, Section 409). A tolerance must be defined for any pesticide used on food crops. Tolerance concentrations on RACs are based on the result of field trials conducted by pesticide manufacturers and are designed to reflect the highest residue concentrations likely under normal agricultural practice. Thus, tolerances are based on good agricultural practice rather than on considerations of human health. The determination of what might be a safe level of residue exposure is made by considering the results of toxicological studies of the pesticide's effects on animals and, when data are available, on humans. Both acute and chronic effects, including cancer, are considered, although currently, acute effects are treated separately. These data are used to establish human exposure guidelines (i.e., 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 residues in the foods (i.e., Theoretical Maximum Residue Contributions, TMRCs). If the TMRCs exceed the RfD, then anticipated residues are calculated and compared with the proposed tolerance. The percent of crop acreage treated is also considered. If the anticipated residues exceed the RfD, then the proposed tolerance is rejected, and the manufacturer may recommend a new level. Tolerances are the single most important tool by which the U.S. Government regulates pesticide residues in food. More than 8,500 food tolerances for all 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). Table 1-1 shows the number of tolerances established for insecticides, herbicides, and fungicides in the mid-1980s for purposes of comparison. APPROACH TO THE STUDY Infants and children are unique. They are undergoing growth and development. Their metabolic rates are rapid. Their diets and their patterns

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Pesticides in the Diets of Infants and Children TABLE 1-1 Food Tolerances Established Under Sections 408 and 409 of the Federal Food, Drug, and Cosmetic Act   Number of Tolerances Under: Type of Pesticide Section 408 Section 409 Insecticides 3,654 63 Herbicides 2,462 39 Fungicides 1,256 20 Total 7,372 122 NOTE: This table does not include feed-additive tolerances listed in the CFR. SOURCE: NRC, 1987. of dietary exposure to pesticide residues are quite different from those of adults. To determine whether the current regulatory system in the United States adequately protects infants and children against dietary residues of pesticides, the committee considered two main issues—susceptibility and exposure: Susceptibility: Are infants and children more or less susceptible (sensitive) than adults to the toxic effects of pesticides? Is there a uniform and predictable difference in susceptibility, or must each pesticide (and each toxic response) be considered separately? Does susceptibility increase during periods of rapid growth and development? Does high metabolic activity lead to more rapid excretion of xenobiotic compounds and thus to reduced susceptibility? Is the ability to repair damaged tissues and organs greater in childhood, thus leading to apparently lower sensitivity? In what fashion does the potentially long life span of infants and children affect their susceptibility to diseases with long latent periods? Exposure: What foods do infants and children eat? How much of these foods do they eat? How much variation in diet is there among children in the United States? How much, and what residues are found in or on the food eaten by infants and children? What are the nonfood sources of pesticide exposure? How important are they? What data are available on exposure? Are there adequate, frequently collected food consumption data categorized by age, sex, and race that can serve as a basis for computations of intakes by potentially more sensitive subgroups in the population? What are the proper measures of exposure? The committee examined current procedures for toxicity testing of pesticides

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Pesticides in the Diets of Infants and Children to learn whether these approaches provide sufficient information on toxicity in the young. Specific questions posed by the committee included: How are toxic effects identified? If they are determined by experiments in laboratory animals, what problems exist in transferring the results to humans? To infants and children? What information on toxicity is needed? For example, is information on mechanisms of action needed to establish risks to children? Are animal studies on weanlings and older animals adequate to estimate toxicity in infants and children at relatively earlier stages of development? Are there toxicities unique to some species of laboratory animals? To humans? How can exposures of animals to toxicants late in life predict responses in humans exposed early in life? The committee reviewed approaches to pesticide risk assessment to assess whether these approaches adequately consider the effects of exposure in young age groups. Specific issues included: How is exposure to pesticide residues associated with response? If special consideration needs to be given to childhood exposures that result in risk, how can laboratory data from lifetime animal studies be used to develop meaningful estimates? Does risk accumulate faster during the early years of life? When exposure to a pesticide leads to more than one toxic responses, how can, or should, the total toxicity be described or evaluated? Two final issues that the committee considered were: How can the lifetime risks associated with exposures to pesticides and other chemicals during infancy and childhood be assessed? How can methods for assessing and controlling these risks be improved? In this report, the committee considers the development of children from the last trimester of gestation (26 weeks) through adolescence—approximately 18 years of age. Twenty-six weeks of gestation is considered the beginning of infancy because this age coincides closely with the earliest point at which an infant can survive outside the uterus. All major organ systems can function independently at that point, and the lungs have developed to the degree that reasonable exchanges of oxygen and carbon dioxide can take place. Chapters 2, 3, and 4 of the report consider the susceptibility of infants and children to pesticides. Chapter 2 examines current evidence on the impact of children's exposures to pesticides and other toxicants in light of the special demands imposed by their rapid development, their special nutritional requirements, and their rapid metabolism. Chapter 3 explores current data on perinatal and pediatric toxicity. In Chapter 4, the committee reviews EPA's current and proposed toxicity testing requirements for pesticide registration and tolerance setting.

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Pesticides in the Diets of Infants and Children Chapters 5, 6, and 7 assess the dietary exposure of infants and children to pesticides. The committee began this examination by reviewing in Chapter 5 the food consumption patterns of this age group and exploring the ways that the patterns differ from those of adults—not only in the types and amounts of food and water consumed, but also in the proportion of the diet comprising certain foods. Then in Chapter 6 the committee reviews the data available on pesticide residues in food and gives particular attention to sampling of the foods consumed most by infants and children. In Chapter 7, the committee ties together the information on dietary patterns and residue levels from the two preceding chapters and provides examples for estimating the dietary pesticide exposures of infants and children. This linking of the data on dietary patterns of infants and children with data on pesticide residue levels was accomplished by applying a computer-based technology that enabled the committee to examine and quantify the full range of dietary pesticide exposures. This methodologic innovation obviates the need to study the average exposure of the hypothetical "normal" child and focuses instead on the full distribution of exposures. In Chapter 8, the committee focuses on risk assessment. Using the data developed in Chapters 5, 6 and 7 on exposure levels, the committee presents a new method that can be used by government regulatory agencies to assess the health risks to infants and children resulting from exposures to pesticide residues in the diet. Like the exposure assessment method developed in Chapter 7, the risk assessment method permits examination of the full range of risks across the entire pediatric population. This report embodies three unique features: It is the first assessment of dietary exposures to pesticides that has focused specifically on infants and children. It makes the case that children are different from the rest of the population, both in their vulnerability to toxicants as well as in their patterns of dietary exposure to pesticide residues. Children therefore deserve specific attention in the risk assessment and regulatory processes. It considers the total distribution of dietary exposures to pesticides among infants and children. It does not focus merely on average exposure, nor does it simply use summary statistics to examine the pesticide exposures of a hypothetical "average" child. Instead, through the use of newly applied statistical techniques, the committee was able to examine and quantify the entire range of exposures confronting the pediatric population of the United States. In this way, the committee was able to develop improved estimates of the numbers of children with high levels of dietary exposure to pesticides. This approach should be of considerable value to

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Pesticides in the Diets of Infants and Children the government regulatory agencies, especially EPA, as they continue their efforts to use risk assessment methodologies to safeguard the health of the U.S. population. It proposes new cancer risk assessment methods that take into account temporal patterns of exposure to pesticide residues in the diet of infants and children, as well as tissue growth and changes in cell kinetics with age. Because of their greater consumption of certain foods relative to body weight, children may be at greater risk than adults from pesticides with carcinogenic potential. Infants and children are subject to rapid tissue growth and development, which will have an impact on cancer risk. This report indicates how such variations in exposure with age can be accommodated in the Moolgavkar-Venzon-Knudson model of carcinogenesis (Moolgavkar et al., 1988), along with data on tissue growth and changes in cell kinetics. The methods proposed here can be adapted and extended, based on the availability of appropriate data on dietary exposure to pesticides and on tissue growth and cell kinetics, to arrive at improved estimates of lifetime cancer risks that may be posed by dietary exposure to pesticides. REFERENCES Block, G., B. Patterson, and A. Subar. 1992. Fruit, vegetables, and cancer prevention: A review of the epidemiological evidence. Nutr. Cancer 18:1–29. EPA (U.S. Environmental Protection Agency). 1992. Pesticide Industry Sales and Usage. 1990 and 1991 Market Estimates. Office of Pesticide Programs. Washington, D.C.: U.S. Environmental Protection Agency. Mason, A.F. 1928. Spraying, Dusting, and Fumigating of Plants. New York: Macmillan. McCallan, S.E.A. 1967. History of fungicides. In Fungicides: An Advanced Treatise, Vol. 1, D.C. Torgeson, ed. New York: Academic. Moolgavkar, S.H., A. Dewanji, and D.J. Venzon. 1988. A stochastic two-stage model for cancer risk assessment. I. The hazard function and the probability of tumor. Risk Anal. 8:383–392. NRC (National Research Council). 1987. Regulating Pesticides in Food: The Delaney Paradox . Washington, D.C.: National Academy Press. 288 pp. Wilkinson, C.F. 1990. Introduction and overview. Pp. 5–33 in Advances in Modern Environmental Toxicology: The Effects of Pesticides on Human Health, Vol. XVIII, S.R. Baker and C.F. Wilkinson, eds. Princeton, N.J.: Princeton Scientific. 438 pp.