Approaches for assessing risks to sensitive populations: lessons learned from evaluating risks in the pediatric population.

Assessing the risk profiles of potentially sensitive populations requires a "tool chest" of methodological approaches to adequately characterize and evaluate these populations. At present, there is an extensive body of literature on methodologies that apply to the evaluation of the pediatric population. The Health and Environmental Sciences Institute Subcommittee on Risk Assessment of Sensitive Populations evaluated key references in the area of pediatric risk to identify a spectrum of methodological approaches. These approaches are considered in this article for their potential to be extrapolated for the identification and assessment of other sensitive populations. Recommendations as to future research needs and/or alternate methodological considerations are also made.

[1]  W. Slikker,et al.  Incorporating children's toxicokinetics into a risk framework. , 2004, Environmental health perspectives.

[2]  Philip J. Landrigan,et al.  Biological markers in environmental health research , 1987 .

[3]  T. Kamataki,et al.  Four Forms of Cytochrome P‐450 in Human Fetal Liver: Purification and Their Capacity to Activate Promutagens , 1991, Japanese journal of cancer research : Gann.

[4]  Richard Reiss,et al.  A framework and case study for exposure assessment in the Voluntary Children's Chemical Evaluation Program. , 2003, Risk analysis : an official publication of the Society for Risk Analysis.

[5]  E. Delvin,et al.  Congenital hypothyroidism: from paracelsus to molecular diagnosis. , 2006, Clinical biochemistry.

[6]  A. Faden,et al.  Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP. , 2006, CNS drug reviews.

[7]  T. Hammond,et al.  Differential effects of two NMDA receptor antagonists on cognitive-behavioral development in nonhuman primates I. , 2001, Neurotoxicology and teratology.

[8]  A. Done Developmental pharmacology , 1964, Clinical pharmacology and therapeutics.

[9]  A. Bleyer,et al.  Cancer in 15- to 29-year-olds by primary site. , 2006, The oncologist.

[10]  D. Hewitt,et al.  A survey of childhood malignancies. , 1962, British medical journal.

[11]  Ronald N Hines,et al.  The ontogeny of drug metabolism enzymes and implications for adverse drug events. , 2008, Pharmacology & therapeutics.

[12]  B. D. Beck,et al.  The development of a stochastic physiologically-based pharmacokinetic model for lead. , 2001, The Science of the total environment.

[13]  Jane Alcorn,et al.  Ontogeny of Hepatic and Renal Systemic Clearance Pathways in Infants Part I , 2002, Clinical pharmacokinetics.

[14]  E. Hall,et al.  Lessons we have learned from our children: cancer risks from diagnostic radiology , 2002, Pediatric Radiology.

[15]  R. Brent,et al.  Utilization of developmental basic science principles in the evaluation of reproductive risks from pre- and postconception environmental radiation exposures. , 1999, Teratology.

[16]  J. Wehner,et al.  Effects of sodium ascorbate, sodium saccharin and ammonium chloride on the male rat urinary bladder. , 1995, Carcinogenesis.

[17]  John C Lipscomb,et al.  Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. , 2007, Current drug metabolism.

[18]  Harvey J Clewell,et al.  Evaluation of the potential impact of age- and gender-specific pharmacokinetic differences on tissue dosimetry. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[19]  D. Cory-Slechta Studying toxicants as single chemicals: does this strategy adequately identify neurotoxic risk? , 2005, Neurotoxicology.

[20]  O. Niwa,et al.  Chromosome Aberrations do not Persist in the Lymphocytes or Bone Marrow Cells of Mice Irradiated In Utero or Soon after Birth , 2007, Radiation research.

[21]  J. Issa,et al.  Age-Related DNA Methylation Changes in Normal Human Prostate Tissues , 2007, Clinical Cancer Research.

[22]  J. Stevens,et al.  Epirubicin Glucuronidation and UGT2B7 Developmental Expression , 2006, Drug Metabolism and Disposition.

[23]  D. Eaton Biotransformation enzyme polymorphism and pesticide susceptibility. , 2000, Neurotoxicology.

[24]  B. Ames,et al.  Chemical carcinogenesis: too many rodent carcinogens. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[25]  J. Olsen,et al.  GENETIC EFFECTS OF RADIOTHERAPY FOR CHILDHOOD CANCER , 2003, Health physics.

[26]  B. Sonawane,et al.  A lifestage-specific approach to hazard and dose-response characterization for children's health risk assessment. , 2008, Birth defects research. Part B, Developmental and reproductive toxicology.

[27]  A. Glazko,et al.  Chloramphenicol in the newborn infant. A physiologic explanation of its toxicity when given in excessive doses. , 1960, The New England journal of medicine.

[28]  V G Zartarian,et al.  Children's exposure assessment: a review of factors influencing Children's exposure, and the data available to characterize and assess that exposure. , 2000, Environmental health perspectives.

[29]  D. Bell,et al.  Genetic susceptibility: significance in risk assessment. , 1998, Toxicology letters.

[30]  Human toxicity of PBDDs and PBDFs. , 1995, Environmental health perspectives.

[31]  J. Pin,et al.  Pharmacology and functions of metabotropic glutamate receptors. , 1997, Annual review of pharmacology and toxicology.

[32]  Louis W. Chang,et al.  Handbook of Developmental Neurotoxicology , 1998 .

[33]  Dana B. Barr,et al.  Biologic Monitoring of Exposure to Environmental Chemicals throughout the Life Stages: Requirements and Issues for Consideration for the National Children’s Study , 2005, Environmental health perspectives.

[34]  S. Bonassi,et al.  Children's exposure to environmental pollutants and biomarkers of genetic damage. I. Overview and critical issues. , 2006, Mutation research.

[35]  Fan Wang,et al.  DNA Repair Gene XPD Polymorphisms and Cancer Risk: A Meta-analysis Based on 56 Case-Control Studies , 2008, Cancer Epidemiology Biomarkers & Prevention.

[36]  Walter Schmitt,et al.  A Mechanistic Approach for the Scaling of Clearance in Children , 2006, Clinical pharmacokinetics.

[37]  D. G. McCarver,et al.  Applicability of the principles of developmental pharmacology to the study of environmental toxicants. , 2004, Pediatrics.

[38]  P. Wedlund The CYP2C19 Enzyme Polymorphism , 2000, Pharmacology.

[39]  Lindsey A. Torre,et al.  Cancer Facts and Figures for Hispanics/Latinos 2015-2017 , 1905 .

[40]  O. Pelkonen,et al.  Characterization of human fetal hepatic cytochrome P-450-associated 7-ethoxyresorufin O-deethylase and aryl hydrocarbon hydroxylase activities by monoclonal antibodies. , 1987, Developmental pharmacology and therapeutics.

[41]  R W Miller,et al.  Childhood and adult cancer after intrauterine exposure to ionizing radiation. , 1999, Teratology.

[42]  P G Mulder,et al.  Immunologic effects of background exposure to polychlorinated biphenyls and dioxins in Dutch preschool children. , 2000, Environmental health perspectives.

[43]  Melvin E Andersen,et al.  Dose-dependent transitions in mechanisms of toxicity. , 2004, Toxicology and applied pharmacology.

[44]  T. Guilarte Pb2+ inhibits NMDA receptor function at high and low affinity sites: developmental and regional brain expression. , 1997, Neurotoxicology.

[45]  Peter Wood,et al.  The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. , 2005, Blood.

[46]  G. Kearns,et al.  Cisapride disposition in neonates and infants: in vivo reflection of cytochrome P450 3A4 ontogeny , 2003, Clinical pharmacology and therapeutics.

[47]  A. Tward,et al.  Toxicity of chlorpyrifos and chlorpyrifos oxon in a transgenic mouse model of the human paraoxonase (PON1) Q192R polymorphism , 2005, Pharmacogenetics and genomics.

[48]  Henrik Toft Sørensen,et al.  The Danish National Birth Cohort - its background, structure and aim , 2001, Scandinavian journal of public health.

[49]  Ling-Zhi Wang,et al.  A warfarin‐dosing model in Asians that uses single‐nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9 , 2006, Clinical pharmacology and therapeutics.

[50]  E. Boersma,et al.  Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins. Consequences for longterm neurological and cognitive development of the child lactation. , 2000, Advances in experimental medicine and biology.

[51]  C. Kimmel,et al.  Children's health risk assessment: incorporating a lifestage approach into the risk assessment process. , 2008, Birth defects research. Part B, Developmental and reproductive toxicology.

[52]  H. Nakanishi,et al.  Involvement of enhanced sensitivity of N-methyl-d-aspartate receptors in vulnerability of developing cortical neurons to methylmercury neurotoxicity , 2001, Brain Research.

[53]  John Balbus,et al.  CHILDREN's SUSCEPTIBILITY TO CHEMICALS: A REVIEW BY DEVELOPMENTAL STAGE , 2004, Journal of toxicology and environmental health. Part B, Critical reviews.

[54]  A. Herbst,et al.  Adenocarcinoma of the vagina. Association of maternal stilbestrol therapy with tumor appearance in young women. , 1971, The New England journal of medicine.

[55]  R. Scheuplein,et al.  Differential Sensitivity of Children and Adults to Chemical Toxicity , 2004, Human and Ecological Risk Assessment: An International Journal.

[56]  J. Xue,et al.  Identifying Childhood Age Groups for Exposure Assessments and Monitoring , 2007, Risk analysis : an official publication of the Society for Risk Analysis.

[57]  David R. Williams,et al.  Vulnerability as a Function of Individual and Group Resources in Cumulative Risk Assessment , 2007, Environmental health perspectives.

[58]  J. Lipscomb,et al.  Covariation of Human Microsomal Protein Per Gram of Liver with Age: Absence of Influence of Operator and Sample Storage May Justify Interlaboratory Data Pooling , 2008, Drug Metabolism and Disposition.

[59]  Dale Hattis,et al.  Physiologically Based Pharmacokinetic (PBPK) Modeling of Caffeine and Theophylline in Neonates and Adults: Implications for Assessing Children's Risks from Environmental Agents , 2004, Journal of toxicology and environmental health. Part A.

[60]  L. Anderson,et al.  Critical windows of exposure for children's health: cancer in human epidemiological studies and neoplasms in experimental animal models. , 2000, Environmental health perspectives.

[61]  W. Evans,et al.  Liver volume as a determinant of drug clearance in children and adolescents. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[62]  S. Bonassi,et al.  Children's exposure to environmental pollutants and biomarkers of genetic damage. II. Results of a comprehensive literature search and meta-analysis. , 2006, Mutation research.

[63]  M. Siimes,et al.  Reproduction following treatment for childhood leukemia: a population-based prospective cohort study of fertility and offspring. , 1991, Medical and pediatric oncology.

[64]  Amy D. Kyle,et al.  Integrated Assessment of Environment and Health: America’s Children and the Environment , 2005, Environmental Health Perspectives.

[65]  R. Luebke,et al.  Suppression of Immune Function and Susceptibility to Infections in Humans: Association of Immune Function with Clinical Disease , 2004, Journal of immunotoxicology.

[66]  U. Klotz,et al.  P-glycoprotein function in the elderly , 2004, European Journal of Clinical Pharmacology.

[67]  Y. Turpaz,et al.  CYP4F2 genetic variant alters required warfarin dose. , 2008, Blood.

[68]  T. Cresteil,et al.  Evidence of impaired cisapride metabolism in neonates. , 2001, British journal of clinical pharmacology.

[69]  T. Tammela,et al.  Is the incidence of hypospadias increasing? Analysis of Finnish hospital discharge data 1970-1994. , 2000, Environmental health perspectives.

[70]  L. Goldman Children--unique and vulnerable. Environmental risks facing children and recommendations for response. , 1995, Environmental health perspectives.

[71]  R. Brent,et al.  A pediatric perspective on the unique vulnerability and resilience of the embryo and the child to environmental toxicants: the importance of rigorous research concerning age and agent. , 2004, Pediatrics.

[72]  E. Boersma Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins , 2001 .

[73]  G W Kneale,et al.  Radiation dose effects in relation to obstetric x-rays and childhood cancers. , 1970, Lancet.

[74]  J. Byrne Long-term genetic and reproductive effects of ionizing radiation and chemotherapeutic agents on cancer patients and their offspring. , 1999, Teratology.

[75]  S G Selevan,et al.  Identifying critical windows of exposure for children's health. , 2000, Environmental health perspectives.

[76]  DNA repair, genetic instability, and cancer , 2007 .

[77]  A. J. Scheetz,et al.  Modulation of NMDA receptor function: implications for vertebrate neural development , 1994, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[78]  K. C. Kanelakis,et al.  Tissue- and gender-specific expression of N-acetyltransferase 2 (Nat2*) during development of the outbred mouse strain CD-1. , 2000, Drug metabolism and disposition: the biological fate of chemicals.

[79]  L. Goldman,et al.  Serum polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans among people eating contaminated home-produced eggs and beef. , 1999, Environmental health perspectives.

[80]  G. Kimmel An overview of children as a special population--relevance to predictive biomarkers. , 2005, Toxicology and applied pharmacology.

[81]  T. Todani,et al.  Liver volume in children measured by computed tomography , 1997, Pediatric Radiology.

[82]  T. Hammond,et al.  Differential effects of two NMDA receptor antagonists on cognitive--behavioral performance in young nonhuman primates II. , 2001, Neurotoxicology and teratology.

[83]  B. Sonawane,et al.  A framework for assessing risks to children from exposure to environmental agents. , 2004, Environmental health perspectives.

[84]  H. Özkaynak,et al.  Exposure Assessment Implications for the Design and Implementation of the National Children’s Study , 2005, Environmental health perspectives.

[85]  R. Albertini,et al.  The Use of Biomonitoring Data in Exposure and Human Health Risk Assessments , 2006, Environmental health perspectives.

[86]  J. Burke,et al.  The challenge of assessing children's residential exposure to pesticides , 2000, Journal of Exposure Analysis and Environmental Epidemiology.

[87]  A. Fantel,et al.  Human embryonic cytochrome P450S: phenoxazone ethers as probes for expression of functional isoforms during organogenesis. , 1991, Biochemical pharmacology.

[88]  G. Kearns,et al.  Cytochrome P450 Involvement in the biotransformation of cisapride and racemic norcisapride in vitro: differential activity of individual human CYP3A isoforms. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[89]  S. Holgate,et al.  Environmental risk factors and allergic bronchial asthma , 2005, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[90]  B. Lin,et al.  Slow acetylator mutations in the human polymorphic N-acetyltransferase gene in 786 Asians, blacks, Hispanics, and whites: application to metabolic epidemiology. , 1993, American journal of human genetics.

[91]  C. Willhite,et al.  Derivation of a Bisphenol a Oral Reference Dose (RfD) and Drinking-Water Equivalent Concentration , 2008, Journal of toxicology and environmental health. Part B, Critical reviews.

[92]  Michael Dourson,et al.  Differential sensitivity of children and adults to chemical toxicity. I. Biological basis. , 2002, Regulatory toxicology and pharmacology : RTP.

[93]  Q. Fernaǹdo Metal speciation in environmental and biological systems. , 1995, Environmental health perspectives.

[94]  J. Hakkola,et al.  Expression of xenobiotic-metabolizing cytochrome P450 forms in human adult and fetal liver. , 1994, Biochemical pharmacology.

[95]  R. Smialowicz,et al.  Development of the murine and human immune system: differential effects of immunotoxicants depend on time of exposure. , 2000, Environmental health perspectives.

[96]  M. Morandi,et al.  Exposure Assessment in the National Children’s Study: Introduction , 2005, Environmental health perspectives.

[97]  M. Ticku,et al.  Ethanol and Regulation of the NMDA Receptor Subunits in Fetal Cortical Neurons , 1998, Journal of neurochemistry.

[98]  Richard D. Wood,et al.  Nucleotide Excision Repair in Mammalian Cells* , 1997, The Journal of Biological Chemistry.

[99]  J. Neel,et al.  Changing perspectives on the genetic doubling dose of ionizing radiation for humans, mice, and Drosophila. , 1999, Teratology.

[100]  R. Brent,et al.  The Vulnerability, Sensitivity, and Resiliency of the Developing Embryo, Infant, Child, and Adolescent to the Effects of Environmental Chemicals, Drugs, and Physical Agents as Compared to the Adult , 2004, Pediatrics.

[101]  T. Chang,et al.  Cumulative environmental changes, skewed antigen exposure, and the increase of allergy. , 2008, Advances in immunology.

[102]  R. Connelly,et al.  Cancer in offspring of long‐term survivors of childhood and adolescent cancer , 1988 .

[103]  Ronald N Hines,et al.  Human hepatic CYP2E1 expression during development. , 2003, The Journal of pharmacology and experimental therapeutics.

[104]  C Timchalk,et al.  A Physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model for the organophosphate insecticide chlorpyrifos in rats and humans. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[105]  E. Mayatepek,et al.  Transient trimethylaminuria in childhood , 1998, Acta paediatrica.

[106]  Division on Earth Pesticides in the Diets of Infants and Children , 1993 .

[107]  K Krishnan,et al.  Modeling interchild differences in pharmacokinetics on the basis of subject-specific data on physiology and hepatic CYP2E1 levels: a case study with toluene. , 2006, Toxicology and applied pharmacology.

[108]  David H. Chen,et al.  The Comparative Immunotoxicity of Five Selected Compounds Following Developmental or Adult Exposure , 2006, Journal of toxicology and environmental health. Part B, Critical reviews.

[109]  Ja Wilson,et al.  Principles and practice of screening for disease , 1968 .

[110]  E. Faustman,et al.  Mechanisms underlying Children's susceptibility to environmental toxicants. , 2000, Environmental health perspectives.

[111]  Jennifer Seed,et al.  Overview: Using Mode of Action and Life Stage Information to Evaluate the Human Relevance of Animal Toxicity Data , 2005, Critical reviews in toxicology.

[112]  M. Wei,et al.  Effects of co-administration of antioxidants and arsenicals on the rat urinary bladder epithelium. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[113]  E. Hubal,et al.  Measuring Potential Dermal Transfer of a Pesticide to Children in a Child Care Center , 2005, Environmental health perspectives.

[114]  R. Brent LAURISTON S. TAYLOR LECTURE: FIFTY YEARS OF SCIENTIFIC RESEARCH: THE IMPORTANCE OF SCHOLARSHIP AND THE INFLUENCE OF POLITICS AND CONTROVERSY , 2007, Health physics.

[115]  A. Vingerhoets,et al.  Prenatal diethylstilbestrol exposure and self-reported immune-related diseases. , 1998, European journal of obstetrics, gynecology, and reproductive biology.

[116]  J. Olsen,et al.  Chromosomal abnormalities among offspring of childhood-cancer survivors in Denmark: a population-based study. , 2004, American journal of human genetics.

[117]  M. Piccinni,et al.  Role of hormone-controlled Th1- and Th2-type cytokines in successful pregnancy , 2000, Journal of Neuroimmunology.

[118]  Chronic Disease Division Cancer facts and figures , 2010 .

[119]  J. V. van Engelen,et al.  Risk assessment of chemicals and pharmaceuticals in the pediatric population: a workshop report. , 2005, Regulatory toxicology and pharmacology : RTP.

[120]  S. Lewis,et al.  The comparative radiation genetics of humans and mice. , 1990, Annual review of genetics.

[121]  A. Stewart The carcinogenic effects of low level radiation. A re-appraisal of epidemiologists methods and observations. , 1973, Health physics.

[122]  Amin Rostami-Hodjegan,et al.  Prediction of the Clearance of Eleven Drugs and Associated Variability in Neonates, Infants and Children , 2006, Clinical pharmacokinetics.

[123]  Rodney R. Dietert,et al.  Lead and Immune Function , 2006, Critical reviews in toxicology.

[124]  J. Olney,et al.  Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. , 1999, Science.

[125]  R. Brent Biological Factors Related to Male Mediated Reproductive and Developmental Toxicity , 1994 .

[126]  S. Cohen,et al.  Tumorigenicity of sodium ascorbate in male rats. , 1998, Cancer research.

[127]  G. B. Louis,et al.  Principles for evaluating health risks in children associated with exposure to chemicals , 2006 .

[128]  Jacqueline Moya,et al.  A lifestage approach to assessing children's exposure. , 2008, Birth defects research. Part B, Developmental and reproductive toxicology.

[129]  T. Stephenson How children's responses to drugs differ from adults. , 2005, British journal of clinical pharmacology.

[130]  D. Bellinger Children's cognitive health: the influence of environmental chemical exposures. , 2007, Alternative therapies in health and medicine.

[131]  R. Dingledine,et al.  The glutamate receptor ion channels. , 1999, Pharmacological reviews.

[132]  A. Rettie,et al.  Developmental Expression of Human Hepatic CYP2C9 and CYP2C19 , 2004, Journal of Pharmacology and Experimental Therapeutics.

[133]  C. Kimmel,et al.  Developmental stage sensitivity and mode of action information for androgen agonists and antagonists. , 2001, The Science of the total environment.

[134]  R. Nygaard,et al.  Second Malignant Neoplasms in Patients Treated for Childhood Leukemia: A Population‐based Cohort Study from the Nordic Countries , 1991, Acta paediatrica Scandinavica.

[135]  Jun-yan Hong,et al.  Genetic polymorphism of cytochrome P450 as a biomarker of susceptibility to environmental toxicity. , 1997, Environmental health perspectives.

[136]  C. Bearer,et al.  How are children different from adults? , 1995, Environmental health perspectives.

[137]  A. Tward,et al.  Expression of human paraoxonase (PON1) during development. , 2003, Pharmacogenetics.

[138]  M. Piepenbrink,et al.  Perinatal Immunotoxicity: Why Adult Exposure Assessment Fails to Predict Risk , 2005, Environmental health perspectives.

[139]  Harvey J Clewell,et al.  Bayesian Estimation of Pharmacokinetic and Pharmacodynamic Parameters in a Mode‐of‐Action‐Based Cancer Risk Assessment for Chloroform , 2007, Risk analysis : an official publication of the Society for Risk Analysis.

[140]  Dale L Preston,et al.  Solid cancer incidence in atomic bomb survivors exposed in utero or as young children. , 2008, Journal of the National Cancer Institute.

[141]  Harvey J Clewell,et al.  Perchlorate and Radioiodide Kinetics Across Life Stages in the Human: Using PBPK Models to Predict Dosimetry and Thyroid Inhibition and Sensitive Subpopulations Based on Developmental Stage , 2007, Journal of toxicology and environmental health. Part A.