Infants and children are not little adults. They are uniquely vulnerable to environmental toxicants. To protect infants and children against toxicants, the National Research Council in 1993 called for development of an approach to risk assessment that considers children's unique patterns of exposure and their special vulnerabilities to pesticides. Many aspects of that call were codified into federal law in the Food Quality Protection Act (FQPA) of 1996. This report highlights the central elements needed for development of a child-protective approach to risk assessment: a) improved quantitative assessment of children's exposures at different life stages, from fetal life through adolescence, including acute and chronic exposures, exposures via multiple routes, and exposures to multiple agents; b) development of new approaches to toxicity testing of chemicals that can detect unanticipated and subtle outcomes and that evaluate experimental subjects over the entire life span from early exposure to natural death to replicate the human experience; c) development of new toxicodynamic and toxicokinetic models that account for the unique physiologic characteristics of infants and children; d) development of new approaches to assessment of outcomes, functional, organ, cellular and molecular, over the entire life span; these measures need to be incorporated into toxicity testing and into long-term prospective epidemiologic studies of children; and e) application of uncertainty and safety factors in risk assessment that specifically consider children's risks. Under FQPA, children are presumed more vulnerable to pesticides than adults unless evidence exists to the contrary. Uncertainty and safety factors that are protective of children must therefore be incorporated into risk assessment when data on developmental toxicity are lacking or when there is evidence of developmental toxicity. The adequate protection of children against toxic agents in the environment will require fundamental and far-reaching revisions of current approaches to toxicity testing and risk assessment. Key words: children's environmental health, developmental toxicology, risk assessment, safety factors, toxicity testing. Environ Health Perspect 112:257-265 (2003). doi:10.1289/ehp.6115 available via http://dx.doi.org/[Online 25 November 2003]
Protection of human health against disease and injury caused by toxic chemicals in the environment is the ultimate goal of risk assessment and risk management. Historically, risk assessment focused on adult exposures and toxicities and gave little consideration to vulnerable life stages such as fetal development and early childhood. An emphasis on adult cancer risk and the evolution of methodologies for estimating cancer risks that are different from the methods used to assess other health effects tended to further diminish the importance for risk assessment of children's exposures and outcomes. In addition, the use of default factors based on the healthy young adult did not account adequately for the unique exposures and sensitivities of fetuses, infants, and children (Landrigan and Carlson 1995).
In the past decade, stimulated especially by the 1993 National Research Council (NRC) report on Pesticides in the Diets of Infants and Children [NAS (National Academy of Sciences) 19931, recognition has grown that children are a group within the population who have unique exposures and special vulnerabilities to environmental toxicants. It is now understood that children require an approach to risk assessment that considers their particular characteristics. The present report, developed by the International Life Sciences Institute (ILSI) with support from the U.S. Environmental Protection Agency (U.S. EPA), is intended to consider the elements and structure of a child-protective approach to risk assessment.
The purpose of this article is to introduce a series of reports from an ILSI Workshop on Risk Assessment and Children's Health held in July 2001. This article begins the discussion of child-protective risk assessment by a) summarizing information on the vulnerability of children to agents in the environment; b) presenting a rationale, based on considerations of public health and preventive medicine, for developing an approach to risk assessment that considers the unique exposures and special sensitivities of infants and children; and c) highlighting elements of great importance for a child-protective approach to risk assessment.
The word "children" is used throughout this paper to include all stages of development (fetuses, infants, and children) from conception to 21 years of age.
The Historical Development of Child-Protective Risk Assessment
The National Research Council report on Pesticides in the Diets of Infants and Children. Publication in 1993 of the NRC report on Pesticides in the Diets of Infants and Children (NAS 1993) was critical in raising awareness of the importance for risk assessment of children's environmental health. This report elevated concern on a broad national level about children's special vulnerabilities to environmental agents. It made clear that protection of the health of vulnerable populations would require a new approach to risk assessment.
The NRC report recommended an approach to risk assessment that moved beyond consideration of average exposures based primarily on adult characteristics to-one that accounted for the heterogeneity of exposures and for potential differential sensitivities at various life stages, particularly during prenatal development, infancy, and childhood. The NRC report built on guidelines that the U.S. EPA had published for developmental toxicity risk assessment in 1986 and revised in 1991 (U.S. EPA 1986, 1991). It also built on other published documents such as the ILSI report on Similarities and Differences between Children and Adults: Implications for Risk Assessment (Guzelian et al. 1992).
Infants and children were identified in both the NRC and ILSI reports as groups within the population who require special consideration in risk assessment because of their unique patterns of exposures to environmental hazards and their special vulnerabilities. The NRC report noted that "children are not little adults." It called for the development of new risk assessment methods that would incorporate better data on children's exposures to pesticides along with improved information on the potentially harmful effects of pesticides during fetal development, infancy, and childhood (NAS 1993).
To "provide a more complete characterization of risk," the NRC committee recommended use of exposure distributions rather than point estimates. It noted that levels of exposure could differ by several orders of magnitude between children and adults. The NRC report recommended also that exposure assessment methods be expanded to consider exposures to multiple chemicals with multiple routes of exposure (NAS 1993).
To enhance characterization of the susceptibility of children, the NRC committee recommended the development of physiologically based pharmacokinetic models that could describe the unique features of young, developing humans. To assess the long-term and delayed effects of early exposures, the committee recommended that "it would be desirable to develop bioassay protocols that provide direct information on the relative contribution of exposures at different ages to lifetime risks." The committee called for further development of "appropriate toxicological tests for perinatal and childhood toxicity" to address issues not addressed in current testing guideline protocols (NAS 1993).
The NRC committee concluded that "in the absence of data to the contrary, there should be a presumption of greater risk to infants and children. To validate this presumption, the committee recommended that "the sensitivity of mature and immature individuals should be studied systematically to expand the current limited database as to relative sensitivity."
To provide enhanced protection to children during vulnerable periods of early development, the NRC committee recommended that a child-protective safety factor of up to 10-fold be considered in risk assessment "when there is evidence of developmental toxicity and when data from toxicity testing relative to children are incomplete." The committee noted that it had long been standard practice at the U.S. EPA and U.S. Food and Drug Administration to divide the no-observed-effect-level (NOEL) obtained in animal test results by an uncertainty factor of 100-fold in establishing a reference dose (RfD) for toxic effects other than cancer or heritable mutation. The committee noted that this 100-fold factor comprises two separate factors 10-fold each: one allows for uncertainty in extrapolating data from animals to humans; the second accommodates variation within the human population. The committee acknowledged that "this latter uncertainty factor generally provides adequate protection for infants and children."
Nevertheless, the committee expressed concern that the standard 100-fold safety factor may not always be sufficient to account for unique susceptibilities at particularly sensitive stages of early development. The committee was also concerned about the great gaps that currently exist in developmental toxicity testing data for many chemicals. It was for these reasons that the NRC committee recommended consideration of a third child-protective safety factor in risk assessment.
Food Quality Protection Act of 1996. After publication of the NRC report, the concept that children should be considered more vulnerable to pesticides than adults in the absence of evidence to the contrary was adopted by the U.S. Congress. In 1996, by unanimous vote of both Houses of Congress, the concept was incorporated into the Food Quality Protection Act of 1996 (FQPA 1996), the principal federal statute governing the use of pesticides in agriculture. Major provisions of this act are as follows:
* Standards for pesticide residues in food must be health based. They must be set at levels that ensure a "reasonable certainty of no harm."
* Exposure and vulnerabilities of infants and children must be specifically considered in establishing pesticide residue standards.
* When insufficient data exist to assess the special exposures and/or vulnerabilities of infants and children, an additional 10-fold safety factor must be considered in setting standards.
* Consideration of the potential benefits of pesticides must be limited.
* All pesticide standards must be reviewed every 10 years.
* Endocrine effects of pesticides must be systematically evaluated in toxicity testing.
FQPA incorporates most of the recommendations of the NRC report. It requires that standards for agricultural pesticides be set at levels sufficiently strict to protect the health of infants and children. It directs the U.S. EPA to use an additional 10-fold margin of safety in assessing the risks to infants and children to take into account the potential for prenatal and postnatal toxicity, particularly when the toxicology and exposure databases are judged to be incomplete. The statute authorizes the U.S. EPA to replace this default 10-fold FQPA safety factor with a different factor only if, based on reliable data, the resulting margin would be adequate to protect infants and children. The requirement for the FQPA safety factor was intended by Congress to be a stimulus to the generation of data on developmental toxicology and on early life exposures.
Recently, the U.S. EPA published its final guidance on the application of the additional FQPA safety factor in risk assessment (U.S. EPA 2002a). The agency will apply the additional factor at the beginning of the risk assessment process but recognizes that the intent of the FQPA safety factor overlaps with several uncertainty factors traditionally used to account for data gaps and concerns in the risk assessment process. These include default 10-fold factors to account for: a) the lack of a no observable adverse effect level (NOAEL) (lowest observable adverse effect level to NOAEL factor); b) the lack of chronic exposure data for setting the chronic RfDs and reference concentrations (RfCs) (subchronic to chronic …