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Risk Assessment and Child Health Jonathan M. Samet, MD ABSTRACT. Risk assessment, an approach for organiz of 1996, an amendment to the Food, Drug, and Cos ing information about hazards to health, safety, and the metic Act.1 environment, provides a framework for gauging the As proposed by the 1983 National Research Coun threat to child health from environmental pollutants. A qualitative risk assessment has 4 components: hazard identification, dose-response assessment, exposure as sessment, and risk characterization. In a risk assessment, consideration can be given to a population group that potentially has increased susceptibility, whether arising from having a high level of exposure or from increased cil committee on risk assessment,2 a quantitative risk assessment has 4 elements (Table 1). Judgment as to the presence of a hazard--the hazard identification component--is based on comprehensive review and evaluation of the evidence, with use of criteria for causality of association or similar forms of expert susceptibility to the agent of concern on a biological judgment that evaluate "weight of evidence." The basis. Children have been proposed as being at increased hazard identification component draws on the full risk from some environmental agents, and there has long been concern and debate that the current approach of determining acceptable exposure levels or intake for a person may not yield safe intake limits for infants and children, who may be placed at greater risk than adults because of exposure patterns and inherent susceptibility. The persistence of debate on this critical public health issue reflects, in part, the difficulty of developing suffi ciently sensitive and validated animal bioassays for crit range of evidence, including human studies, animal studies, and other toxicologic data. If the agent is found not to be a hazard, then a quantitative risk estimate generally would not be made. A full quantitative risk assessment moves from hazard identification to risk characterization, jointly using data on exposure along with the exposure-risk relationship to estimate the range of risk posed by ical outcomes. Epidemiologic studies can play only a the agent and the sources and the degree of uncer limited role, given the complexity of establishing cohorts tainty associated with the risk estimate. Uncertainty and tracking exposures from conception forward to as sess risks across the lifespan. Meeting society's call for healthy environments for children poses an extraordi nary challenge to researchers and to the policy makers who seek to develop evidence-based policies to protect children. Pediatrics 2004;113:952-956; risk assessment, dose-response, exposure, environmental pollutants, chil dren's health. refers to what is not known, and assumptions are needed to bridge the gaps in scientific knowledge corresponding to uncertainties. Assumptions made in characterizing the hazards that contribute to uncertainty should be transparent and justified. The consequences of alternative assumptions should be explored in sensitivity analyses that vary key as sumptions to examine their impact on estimates. For ABBREVIATIONS. FQPA, Food Quality Protection Act; EPA, En vironmental Protection Agency; NOAEL, no observed adverse effect level; RfD, reference dose. characterizing risk to a population from an environ mental agent, information is needed on the distribu tion of exposure to the agent (exposure assessment) and on the risk associated with various levels of Risk assessment, an approach for organizing exposure (dose-response assessment). The distribu tion of exposure may be characterized directly using cmcidoaniosafdgesntteehnedtdetsAhuasecctlbaifmhnottpnyeFrefraoedodensnlga,rdltoudmtatephmitausrtareahaenogntelwdivietosnIsiFinndtongd.aovsefetAiteoutsarhhldcotybeereatnioisQsncamctuhkiueidpitnernreapaenthd,sllaatiitahiset,icFtynzeedautpasto,PytnUsrridoormgaocnosvninhfecititeddtniietolhdcdoted,feitissitw,othshShenehaaetesauaneaAttsfmildenlmrtetchashatpRa,m,igf(rtsiorFeonsneod.QapcmiwmteRfluePeuonaidrtAsdrtnelyeiykk)-,nvirouplatottEanihyonsmlnfxapekidcpncipinscoogilmnfteansoesgutlerooaaoeertundcemhfxsrtoptcrmooe,oadeonrxfassdbspipuyttiuahoooerototesrrfoifsocou,eepcurntxhxolheuegp.punerhoomwIotmnspshrpauiuetreehrnhrooceaesyopusnttsemlghitemiooxceah)ppraattuctoomlhthttoisrheenceenueorged-tprmnasbeiaurattmaeaiitpsmnhsdcaikpnewitsava,,eadsataereaitolnyeusdsmfdsedeswinimsioncntmd,ahdaedmteaattneihoortlttareeerf,lsytrec(ahiteeaathboialxgrdlyee.,,ft range may be particularly relevant to risk manage From the Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland. Received for publication Oct 7, 2003; accepted Oct 20, 2003. ment, as those individuals in the upper tail of expo sure may have unacceptable but avoidable risks. Fig ure 1, for example, shows the distribution of radon Reprint requests to (J-M.S.) Department of Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe St, Ste W6041, Baltimore, MD 21205. E-mail: jsamet@jhsph.edu PEDIATRICS (ISSN 0031 4005). Copyright 2004 by the American Acad emy of Pediatrics. concentrations in US homes; the pattern of exposure to radon in homes has this type of shape. The distri bution indicates that all people have some exposure at home, that the typical or average exposure is low. 952 PEDIATRICS Vol. 113 No. 4 April 2004 TABLE 1. Four Steps of Risk Assessment Hazard identification Dose-response Exposure assessment Risk characterization A review of the relevant biological and chemical information bearing on whether an agent may pose a carcinogenic hazard and whether toxic effects in one setting will occur in other settings. The process of quantifying a dosage and evaluating its relationship to the incidence of adverse health effects response. The determination or estimation (qualitative or quantitative) of the magnitude, duration, and route of exposure. An integration and summary of hazard identification, dose-response assessment, and exposure assessment presented with assumptions and uncertainties. This final step provides an estimate of the risk to public health and a framework to define the significance of the risk. Source: National Research Council.2 and that some homes produce exposures that are high and in a range that is considered unacceptable.3 The exposure-response relationship describes how risk varies in relation to exposure (or dose), as seen in Fig 2.3 Exposure reflects contact with the pollutant and generally has units of concentration multiplied by time, whereas dose refers to the material actually entering the body. Dose can be further specified as the biologically relevant dose: that is, the material actually reaching the target site in the body. For airborne lead, for example, exposure would be esti mated as the product of the atmospheric concentra tion with the duration of exposure, whereas dose would be the amount inhaled and then absorbed into the body. Blood lead or bone lead are biomark ers for the dose of lead. Generally, because of the kinds of information available, risk assessments use exposure-response rather than dose-response rela tionships. The shape of the exposure-response relationship reflects the biological process of injury by the en vironmental agent (Fig 2). Key features of the rela tionship include the presence or absence of a thresh old (curve 2 shows a threshold) and the pattern of increase of risk with exposure, and particularly whether the pattern seems linear or nonlinear. Fig 2. Examples of dose-response models used for carcinogens: 1, linear nonthreshold model; 2, linear threshold model; 3, sublinear threshold model; 4, linear nonthreshold model (steeper slope than 1 indicates greater susceptibility); and 5, supralinear non threshold model. Adapted from Samet and Burke.3 Curves 1 and 4 both show linear nonthreshold rela tionships; the steeper slope of curve 4 suggests greater susceptibility, as might be anticipated for exposures of children to some agents. Characteriza tion of the exposure-response relationship is based in all lines of available evidence, including knowl edge of mechanisms of injury and structure-activity relationships, animal bioassays, and human epide miologic studies. For most agents, human data are limited and animal experiments are the principal basis for describing the exposure-response relation ship. Reliance on animal bioassay data brings the obvious uncertainty of extrapolation from various animal species to humans. Moreover, only rarely are animal studies conducted in the range of human exposures; therefore, most often, knowledge of modes of action is used to infer the shape of doseresponse relationships for humans. For cancer, ani mal data are generally analyzed with the assumption of a linear relationship between exposure and risk. The recent assessment of the risks of indoor radon by the Biological Effects of Ionizing Radiation Com mittee VI of the National Research Council is illus trative of a comprehensive risk assessment.4 This risk assessment begins by reviewing the experimental evidence relevant to respiratory carcinogenesis by radon and its radioactive progeny, finding that Fig 1. Distribution of radon levels in US homes.3 SUPPLEMENT 953 knowledge of the mechanism of injury to DNA by a particles suggests a linear nonthreshold relationship. For the United States, information on exposure to radon in indoor environments was obtained through a national survey of indoor radon concentrations. The exposure-response relationship was character ized by comprehensive statistical analysis of data from 11 cohort studies of underground radon-ex posed miners. This analysis led to several statistical models that describe how the risk of lung cancer associated with radon exposure varies with expo sure, the rate at which exposure is received, and the time since the exposure took place. By combining the exposure information with the epidemiologically derived exposure-response models, the committee could estimate the annual burden of lung cancer deaths in the United States from indoor radon, a number estimated as ranging from 15 400 to 21 800. On the basis of the limited epidemiologic data avail able from underground tin miners in China, who previously often began mining as children, and a finding that the excess cancer risk from radon de clines over time, the committee concluded that child hood radon exposure did not increase risk more than exposure at older ages. The report sets out each of the assumptions made in deriving these numbers, along with a quantitative estimate of the uncertainty associated with key parameters. In an example more directly relevant to practicing pediatricians, the Environmental Protection Agency (EPA)5 estimated the burden of lower respiratory illness and of asthma exacerbation associated with exposure at home to secondhand smoke. By the early 1990s, when the agency conducted its risk assess ment, there was strong evidence linking secondhand smoke to these heath effects (ie, the hazard had been confirmed). The quantitative estimation was made using data on the relative risks for asthma onset and for lower respiratory illness and an estimate of the proportion of women of childbearing age who smoked. The risks were characterized by 8000 to 26 000 new cases of asthma annually for children younger than 18 years and 150 000 to 300 000 new respiratory tract infections annually in children younger than 18 months. The attributable risks were driven by parental smoking. In a risk assessment, consideration can be given to a population group that potentially has increased susceptibility, whether arising from having a high level of exposure or from increased susceptibility to the agent of concern on a biological basis. Children, for example, may be at increased risk from some environmental agents both because of generally higher dose levels than adults and because of in creased vulnerability reflecting immature host de fenses and the incomplete development of target organs.6-7 The incremental risk associated with greater exposure would be captured in the exposure distribution for the subpopulation of interest. An increase in biological susceptibility would be re flected in a steeper exposure-response relationship than in the nonsusceptible or general population (Fig 2). SETTING SAFE LIMITS OF EXPOSURE Quantitative risk assessments are performed to assess the magnitude of the risk to population health associated with existing patterns of exposure and the degree to which risk can be reduced by control pro grams. If a threshold is evident, then a general ap proach to setting a limit for exposure is to allow exposure up to some point below the threshold that incorporates uncertainty factors that may be appro priate when such assessments involve extrapolations and/or incomplete data.8-9 If there is no threshold, so that any exposure conveys some risk, then exposure limits are generally set on the basis of acceptability of the residual risks projected after control measures have reduced exposures to the extent possible. Often, in managing risks, other considerations come into play, such as technologic capacity to reduce expo sures, and costs and benefits. For radon, for example, the EPA's guideline for indoor radon, 4 picocuries per liter of air, was reached by balancing the risks at this concentration, the costs and feasibility of lower ing levels below the guideline, and the lack of pre cision of measurements of indoor radon at lower levels. In approaching the setting of safe limits of expo sure for many substances, including pesticides, gov ernmental agents follow formulaic approaches for estimating levels of exposure or dose that will not be harmful to the public health. Generally, statutes con tain language through which Congress guides agen cies in setting such standards. For example, for the major outdoor air pollutants, the Clean Air Act calls for the administrator of the EPA to set standards that provide "an adequate margin of safety." Because human data are available for only a few environmen tal pollutants, as in the example of radon, the iden tification of acceptable levels is based in animal bio assay data. Typically, as seen in Fig 3,10 animal bioassays involve exposures to animals bracketing levels at which responses can be anticipated and at lower levels at which responses are not anticipated. For setting an acceptable level of exposure for the noncancer health effects of specific concern in chil dren, 2 key points are identified in the assay data: 1) the lowest exposure at which an adverse effect is detected, the lowest observed adverse effect level; and 2) the exposure at which no adverse effect is observed, the no observed adverse effect level (NOAEL). To bridge from these points to an acceptable ex posure or intake for a person, the EPA uses reference doses (RfDs) or reference concentrations in setting limits for oral and inhalation exposures to chemicals, respectively. The RfD is calculated with the NOAEL as a starting point, followed by further reductions to take account of sources of uncertainty and vari ability. One evident source of uncertainty to be ad dressed is the extrapolation from an animal bioassay to humans, and another is the possible variability of responses across people. These uncertainties are taken into account in setting acceptable intake limits by dividing the NOAEL by factors for each. The range of factors used for this purpose has varied by 954 RISK ASSESSMENT AND CHILD HEALTH Fig 3. Depiction of a hypothetical doseresponse curve. Data points are repre sented by triangles. The NOAEL is the highest dose that caused no significant ef fects (over background) in offspring. The lowest-observable adverse effect level is the lowest dose that caused significant ef fects (over background) in offspring. The threshold is the calculated lowest point on the dose-response curve at which a dose of test agent would elicit changes in off spring; doses below the threshold will not cause deleterious effects in offspring and should be considered safe.9 agency and country.11 Typically, the NOAEL is di vided by 100, representing assumption of a 10-fold uncertainty for the species extrapolation and an or der of magnitude spread in the variability of respon siveness. This approach is assumed to yield a sub threshold and hence a "safe" exposure or dose. ENSURING SAFETY FOR CHILDREN There has long been concern that this approach may not yield safe intake limits for infants and chil dren, who may be at greater risk than adults because of exposure patterns and inherent susceptibility.1-8 For pesticides in foods, the FQPA places the burden on the administrator of the EPA to determine that "there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures." To achieve this goal, the FQPA of 1996 requires an additional uncer tainty factor of 10 for children in regard to pesticides in foods, unless there are sufficient data to indicate that some other factor will suffice. The FQPA further protects children by requiring the EPA to consider aggregate exposure, that is, the exposure to pesti cides from different routes, and cumulative risk, that is, the "cumulative effects of such residues and other substances that have a common mechanism of toxic ity." The additional uncertainty factor of 10 stems from the National Research Council's 1993 report, "Pesti cides in the Diets of Infants and Children."8 The rationale for this factor lies in the many aspects of development that could contribute to vulnerability of the fetus, infants, and children to chemicals.8-12 In addition, exposures and doses for some agents, eg, lead, may be particularly high for some children, and there could be unanticipated synergism among the various factors, potentially increasing risk for chil dren. Others have argued, on the basis of largely empiric analysis, that this additional factor is not needed.12-15 Those who are critical of the additional FQPA uncertainty factor cite empirical analyses, showing that current practices do not result in inad equate protection against developmental toxicity and also point to evidence that children are not necessar ily and uniformly at greater risk than adults. This debate cannot be resolved readily with avail able data, and the proposition that an additional uncertainty factor is not always needed for children does not exclude the need on a case-by-case basis. The persistence of debate on this critical public health issue reflects the difficulty of developing suf ficiently sensitive and validated animal bioassays for critical outcomes. Epidemiologic studies can play only a limited role, given the complexity of establish ing cohorts and tracking exposures forward from conception and that EPA must make safety decisions for products to which children are not exposed. There are only a few examples of agents for which such studies have been informative (eg, lead, methylmercury), and these examples represent failures of protective approaches. CONCLUSIONS AND RECOMMENDATIONS Meeting society's call for healthy environments for children poses an extraordinary challenge to re searchers and the policy makers who develop evi dence-based policies to protect children. Children have many chemical exposures through food, air, and water, and new chemicals are introduced into the environment at a rapid rate and with little test ing. Windows of vulnerability during development raise concern for susceptibility and for risk for irre versible consequences of early exposures, such as impaired neurocognitive functioning and increased cancer risk. Animal bioassays, the mainstay of test ing, are inherently limited and of uncertain sensitiv ity and relevance. They are costly and cannot feasibly be conducted across the full range of outcomes rele vant to child health. Myriad differences between fe tuses, infants, children, and adults introduce sub stantial uncertainty in extending findings from one group to another. Assumption of an additional un certainty factor, as with the FQPA's factor of 10 for children, seems warranted when the evidence is in complete or uncertain, but the appropriateness of this factor, particularly its assumption for a wide range of exposures and outcomes, is not established. Several lines of research may prove useful and lead to better-informed strategies for protection of children: SUPPLEMENT 955  Additional empirical research, using the animal bioassay data, to assess the degree of protection provided by alternative strategies for use of the evidence in setting RfDs Exposure assessment studies to better characterize exposures of children to chemicals during critical periods Development of sensitive suites of biomarkers Development of surveillance strategies for devel opmental consequences of environmental chemi cals Population-based studies to assess the contribu tions of chemical pollutants to key noncancer health effects, including impaired neurocognitive development This is an ambitious set of recommendations but offers an agenda that needs to be followed if evi dence is to drive our handling of environmental risks to children. Absent this needed evidence, we cannot answer the question posed in the title of this manu script: whether current risk assessment approaches are sufficiently protective of children. REFERENCES 1. Goldman LR, Koduru S. Chemicals in the environment and develop mental toxicity to children: a public health and policy perspective. Environ Health Perspect. 2000;108(suppl 3):443-448 2. National Research Council (NRC), Committee on the Institutional Means for Assessment of Risks to Public Health. Risk Assessment in the Federal Government: Managing the Process. Washington, DC: National Academy Press; 1983 3. Samet JM, Burke TA. Epidemiology and risk assessment. In: Brownson RC, Petitti DB, eds. Applied Epidemiology: Theory to Practice. New York, NY: Oxford University Press; 1998:137-175 4. National Research Council (NRC), Committee on Health Risks of Ex posure to Radon, Board on Radiation Effects Research, Commission on Life Sciences. Health Effects of Exposure to Radon (BEIR VI). Washington, DC: National Academy Press; 1998 5. US Environmental Protection Agency (EPA). Respiratory Health Effects of Passive Smoking: Lung Cancer and Other Disorders. Washington, DC: US Government Printing Office; 1992 (EPA/600/006F) 6. Selevan SG, Kimmel CA, Mendola P. Identifying critical windows of exposure for children's health. Environ Health Perspect. 2000;108(suppl 3):451-455 7. Bruckner JV. Differences in sensitivity of children and adults to chem ical toxicity: the NAS panel report. Regul Toxicol Pharmacol. 2000;31: 280-285 8. National Research Council (NRC). Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations. Washington, DC: National Academy Press; 1993 9. Kammen DM, Hassenzahl DM. Should We Risk It? Exploring Environ mental, Health, and Technological Problem Solving. Princeton, NJ: Princeton University Press; 1999 10. Fan AM, Chang LW. Toxicology and Risk Assessment. Principles, Methods, and Applications. New York, NY: Marcel Dekker; 1996 11. 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