Abstract
The second edition of the Handbook of Developmental Neurotoxicology builds on concepts presented in the first edition that was published 20 years earlier. The majority of the chapters are presented in an easily digestible format of less than 10 pages, with the focus being on updates in the field since the first edition of this book was published. With that in mind, the reader should have a strong foundation in the basics in order to appreciate the current state of the science that is presented in such a concise manner.
Both the first and second editions are organized into 8 parts. Part 1: Cellular and Molecular Morphogenesis of the Nervous System; Part 2: Developmental Neurobiology/Toxicology (Developmental Biology/Toxicology in first edition); Part 3: Synaptogenesis and Neurotransmission; Part 4: Nutrient and Chemical Disposition; Part 5: Behavioral Assessment; Part 6: Clinical Assessment and Epidemiology; Part 7: Specific Neurotoxic Syndromes; Part 8: Risk Assessment. Although the book is divided into the same 8 parts, the chapters within each section are expanded to reflect more recent advances in each subject area. The following summaries provide an overview of the major topics covered in each chapter.
Part 1 includes 4 chapters that provide the current state of the science in neurodevelopment with respect to brain morphogenesis, neural cell adhesion molecules (NCAMs), neurite development, and myelin. The 4 chapters in this section are focused on our current understanding of mechanisms and novel approaches for evaluation. Chapter 1 addresses processes involved in brain morphogenesis and highlights reductionist and holistic approaches as they relate to developmental neurotoxicology. Much of the chapter is focused on holistic approaches such as computational modeling and whole brain assessments in larval zebra fish. The NCAM regulates neurite outgrowth, fasciculation, and target recognition in the developing nervous system by mediating cell adhesion and signal transduction. Additionally, NCAM is the dominant carrier of polysialic acid (PSA), an unusual carbohydrate consisting of long homopolymers of sialic acid. Chapter 2 provides an overview of NCAM and PSA from expression levels during development, role in cell migration, and importance for activity-induced synaptic plasticity. The authors conclude that PSA-NCAM may represent a critical link between cell migration, activation, transmembrane signal transduction, and rapid remodeling of the cell surface. Chapter 3 is a review of our current understanding of neurites (ie, axons or dendrites) and techniques that apply to evaluation of neurite development and developmental toxicology. Included in the discussion are molecular mechanisms underlying neurite growth and applications in neurotoxicology, genetic modulation of neurite development and examples of neurotoxicants that act via this mechanism, cell death mechanisms (ie, apoptosis, autophagy, and necrosis) and neurite development, and their relevance to neurotoxicology, stem/progenitor cells, and neurite development and applications to neurotoxicology, and neurite growth and state-of-the-art techniques (eg, high-content imaging, in vitro 3D models, and nanotechnology). The authors conclude that neurites serve as useful markers of neurotoxic insult, especially when cell death is not an effect. Myelin constitutes nearly half of the brain white matter and even more in peripheral myelinated axons, highlighting its importance in the normal brain development and functioning. Chapter 4 covers the myelin structure, with recent updates (eg, myelin is highly plastic and can play a dynamic role in the learning process), the chemical composition of vertebrate myelin, the function of neuron–glia communication and its regulation, Schwann cell and oligodendrocyte lineages, animal models of dysmyelination and demyelination, the effect of factors such as environmental toxicants, malnutrition, and thyroid deficiency on developmental myelination, remyelination, and current treatments for myelin disorders. The authors highlight the need to better understand the processes and pathways involved in the regulation of myelination during development as well as the need to translate our current understanding of myelin regeneration into remyelination treatments.
Part 2 consists of 9 chapters covering a range of topics relevant to developmental neurobiology and toxicology, including neurotrophic factors, serotonin and embryonic development, neurotoxic and neurotrophic effects of gamma-aminobutyric (GABA)ergic agents on the developing brain, neural stem cell biology, apoptosis, periods of susceptibility, in vitro and in silico modeling, and zebra fish and Caenorhabditis elegans models. The description of the role of neurotrophin signaling in the etiology and treatment of various degenerative and psychiatric disorders was particularly interesting (chapter 5), as well as the overview of the role of serotonin as a morphogen-like signal during development, prior to acting as a neurotransmitter (chapter 6). Chapter 7 highlights the vulnerability of the GABAergic system during neurodevelopment considering that recent discoveries have shown that it starts out as an excitatory neurotransmitter early in development before becoming the principal inhibitory neurotransmitter in the adult central nervous system (CNS). Chapter 8 provides an overview of neural stem cells in the developing and adult brain and highlights their potential as a model for developmental neurotoxicity assessments. The role of apoptosis in the developing nervous system is described in Chapter 9, along with chemicals that trigger neuronal and/or glial cell apoptosis in the developing brain (eg, anesthetics, polychlorinated biphenyls [PCBs], and zinc dyshomeostasis). Chapter 10 provides an overview of developmental milestones during ontogenesis of the CNS. Understanding when certain organs are developing in a particular animal model allows for targeted investigations into agents that may disrupt that developmental event. A very useful summary of milestones (external, histological, and myelination) is presented relative to postfertilization date and compared across species (human, rat, mouse, and monkey). Novel approaches to better understand blood–brain barrier (BBB) permeability are discussed in chapter 11. The current developmental neurotoxicity (DNT) guidelines do not require assessment of chemicals on development of the neurovascular unit, which gives rise to the BBB. This gap in the guideline could lead to overlooking potential events that may not manifest as obvious defects. The pros and cons of in vitro and in silico approaches are presented as possible approaches to be further developed to predict chemical disruptors of BBB development. The zebra fish model offers an alternative vertebrate animal model for developmental biology and toxicology research and is amenable to high-throughput screening (chapter 12). It is particularly interesting that zebra fish have a developmentally and functionally similar BBB to other vertebrates, and this barrier may have a protective role against neurotoxicants. Applications in chemical screening are discussed, including the Fish Embryo Acute Toxicity Test, morphological screens, and behavioral assays. Part 2 ends with an overview of the nematode model, C elegans, as a model system for preliminary evaluations. Screening in the C elegans model may help researchers focus efforts on specific mechanisms (eg, oxidative stress, dopaminergic degeneration, and epigenetic changes) in subsequent studies (chapter 13).
Part 3 consists of 5 chapters that include topics such as human 3D in vitro models for developmental neurotoxicity, ontogeny of monoamine neurotransmitters, developmental toxicity within the central cholinergic nervous system, ontogeny of second messenger systems, and N-methyl-D-aspartic acid (NMDA) receptors. Chapter 14 addresses some of the deficits of current DNT testing approaches cited in other chapters (eg, cost, time, limited applicability), highlighting the importance of identifying more cost-effective alternatives. One such approach may be 3D cultures that better represent brain tissue in terms of growth, coculture of different cell types, and perfusion for homeostatic nutrient supply. The discussion around mini-brains is fascinating in terms of future possibilities, including combining it with other mini-organs to form a human-on-chip. In chapter 15, the review focuses on monoaminergic development, including synaptogenesis, susceptible periods of development in the rat, and agents that alter these developmental processes. Similarly, in chapter 16, the focus is development of the cholinergic system, critical windows of neurodevelopment, and examples of neurotoxicants that impact development of the cholinergic system (eg, pesticides, nicotine, lead, endocrine disruptors). Chapter 17 tackles what is currently understood about the role of second messengers in signaling pathways. Second messengers, including cyclic adenosine monophosphate, inositol triphosphate, diacylglycerol, calcium, and nitric oxide play pivotal roles in neurodevelopment (eg, neurogenesis, gliogenesis, and apoptosis), and development can be disrupted by any number of external sources (eg, lead and ethanol) that interfere with these pathways. Part 3 concludes with a discussion of the NMDA receptor as one of the most studied glutamatergic receptors and its critical role in neural development, plasticity, learning, memory, and various neurological disorders (eg, schizophrenia).
Part 4 consists of 6 chapters that include topics such as physiologically based pharmacokinetic (PBPK) models, the BBB, nanomaterials, food and nutrient exposure, the microbiome gut–brain axis, and contaminants in breast milk. Chapter 19 provides the reader with an overview of life-stage PBPK models that account for maturation of organ systems and metabolic capacities to predict the pharmacokinetics of chemicals in the fetus or neonate. The PBPK models were presented for known developmental neurotoxicants in animals or humans, including atrazine, chlorpyrifos, deltamethrin, manganese, perchlorate, and iodine. The life-stage models are important for understanding potential exposure as pharmacokinetic studies are not common in the evaluation of drugs/chemicals in pregnant and lactating women or neonates. The models also allow for predictions/comparisons of developmental neurotoxicity risk across species. In chapter 20, the authors highlight critical aspects of BBB development, including the role of astrocytes and pericytes, as well as signaling pathways. There is also discussion of factors that may lead to disruption of the BBB, including drugs of abuse and neurodegenerative diseases. Although chapter 20 focuses more on human BBB development, the material is complimented by a thorough discussion of BBB models (in vitro, in vivo, in silico) outlined in chapter 11. In chapter 21, the unique properties of nanomaterials are discussed in the context of exposure (eg, inhalation, gastrointestinal, and dermal) and potential toxicity. With respect to the CNS, nanoparticles may enter the brain after deposition on the olfactory mucosa following instillation or inhalation, leaving the CNS particularly vulnerable to metal particulate toxicity. Chapter 22 focuses on vitamins and minerals and factors that may impact bioavailability (eg, chemical form of nutrient, nutrient interactions, and physiological factors, including age). Although deficiency is generally more of a problem than toxicity with respect to nutrients, the authors provide a comprehensive table that summarizes several vitamins and minerals, their primary function in the body, and manifestations of both deficiency and toxicity. In chapter 23, recent discoveries are reviewed related to the microbiome (ie, microorganisms within and on the body) and how it can influence distant organs, including the brain. The authors provide a summary of the interrelationships between the gut microbiota and gut–brain axis, including gaps related to the role of the intestinal microbiome in modulating behavior and CNS disorders. Of particular interest is the finding that the microbiota of an individual is established largely during and after birth and is strongly influenced by mode of delivery (ie, vaginal or cesarean section), as well as by various nutritional factors (eg, breastfeeding vs formula). The last chapter of this section (chapter 24) focuses on contaminants in the breast milk and how exposure to these contaminants, both environmental toxicants and maternal medications, may impact neurodevelopment of the nursing infant. Because this field is constantly expanding, the authors recommend checking up-to-date reliable databases (eg, LactMed) to get safety information on medicinal drugs and nonmedicinal substances.
Part 5 consists of 5 chapters that cover topics such as behavioral phenotyping, psychometric tools for evaluation of infant and adolescent nonhuman primates, automated assessment of cognitive function in nonhuman primates, and behavioral outcome as a primary organizing principle for mechanistic data in developmental neurotoxicity. The focus of chapter 25 is behavioral phenotyping in developmental neurotoxicology. The authors describe the methodologic principles that should be applied in behavioral assessment of developmental neurotoxicity, followed by descriptions of both simple unlearned behaviors (eg, activity) and behavioral test batteries that include assessments of more complex behaviors (eg, learning and memory) in rats and mice. The authors emphasize that batteries for screening potential neurotoxicants should be sensitive, reliable, and valid. If initial screens indicate signs of neurotoxicity, further testing should be conducted. In chapter 26, behavioral evaluations appropriate for infant and adolescent nonhuman primates are discussed. Unlike behavioral evaluation of rodents (described in chapter 25) that may have limited applicability to humans, nonhuman primates are a highly relevant and translational animal model for studies on infant and child health. The authors review age- and species-appropriate methods that can be used to evaluate cognition, sensory functioning, and social behavior in young monkeys. Assessment methodologies relevant to evaluating the impact of chemical or drug exposures are highlighted. Chapter 27 builds on the concepts introduced in the prior chapter, focusing on automated assessments of cognitive function in nonhuman primates (late infancy to adulthood). Two automated operant test batteries are discussed that have applicability to nonhuman primates: Cambridge Neuropsychological Test Automated Battery and the US Food and Drug Administration (FDA) National Center for Toxicological Research Operant Test Battery. Operant test methods in nonhuman primates can be used in the evaluation of therapeutic applications, potential novel therapeutic applications, and drugs of abuse. Testing over a prolonged period of development allows researchers to distinguish between developmental delays and effects that may be more permanent in nature. It is not possible to model many neurological disorders in animals considering that they are defined in the clinical literature and are uniquely human. Chapter 28 provides a discussion of the challenges with translating preclinical findings to a clinically relevant effect and serves as an important reminder for anyone designing preclinical studies in this field. The authors highlight the need to understand the correct application of the selected tools as well as their limitations. Chapter 29 raises the issues with sorting through the volume of mechanistic data in an attempt to understand neurobiological mechanisms. The authors suggest that focusing on a single behavioral end point may be a means to selecting a point of departure for developmental neurotoxicity risk assessment. Two examples are provided to illustrate this point. In the first example, rearing behavior is selected to organize the mechanistic studies from the lead exposure literature. In the second example, anxiety behavior as measured in the elevated plus maze is reviewed from studies on bisphenol A. The authors recognize the limitations of this approach (eg, it does not exclude other mechanisms); however, it does offer a promising and more focused approach if the existing literature is sufficient.
Part 6 includes 5 chapters addressing evaluation of the human newborn, neuropsychological assessment of children, neurodevelopmental assessment of the older infant and child, longitudinal studies of the effects of prenatal cocaine exposure, and assessment of case reports and clinical series.
Chapter 30 summarizes some of the tools available for evaluation of a human newborn infant. Evaluation of the newborn reflects (1) the outcome of fetal development; (2) current characteristics, functions, and capacities; and (3) the potential for future development. The authors highlight that the 3 aforementioned facets should guide the evaluation of the newborn. Several measurement tools are outlined, including main outcome measures of pregnancy, Apgar score, neonatal screening programs, neurobehavioral evaluations, neuroimaging, neurophysiological assessments, and perinatal risk factors. No single assessment will provide a complete picture of development; however, combinations of several will improve diagnosis and prediction. Chapter 31 provides an overview of considerations for neuropsychological testing in children, including (1) selecting the age at which assessments should be conducted; (2) assembling the appropriate battery of tests; and (3) addressing practical issues, such as the qualifications of assessors, assessment quality control, and interpretation of exposure–outcome associations in populations. The authors highlight the need to differentiate between the individual risk and population risk, concluding that societal impact of a neurotoxicant exposure could be greatly underestimated if study results are interpreted with only the individual in mind. In chapter 32, the authors discuss the epidemiology of pediatric neurodevelopmental and behavioral disorders (eg, boys are affected at a higher rate, Attention Deficit Hyperactivity Disorder [ADHD] is the most common neurodevelopmental disorder in children) and the types of assessments available for evaluations. The challenges associated with neurodevelopmental assessments and making valid and reliable diagnoses are outlined. The authors present a helpful table outlining specific assessments, the appropriate age group for that evaluation, and a description of the assessment. They also present a table of specific psychosocial, communication, and behavioral measures and how the test is administered (eg, interview form administered by clinician). Chapter 33 discusses the methodological challenges with evaluating prenatal cocaine exposure on development and behavior, including sample selection and comparison groups. The Maternal Health Practices and Child Development Project, designed to address methodological challenges, was a longitudinal investigation of the effects of prenatal cocaine exposure (birth through age 21). In short, the authors note that although the changes associated with prenatal cocaine exposure are subtle and not detectable in any one child, there is evidence for an effect on the development of the CNS. In Chapter 34, case reports and clinical series are discussed as the mechanisms by which unusual patterns of anomalies are described in the medical literature. Case reports are descriptions of anecdotal clinical observations, and a group of cases reported together is a clinical series. Both case reports and clinical series are important means for raising causal hypotheses. Although they may serve as a first step in establishing a possible pattern of behavioral or cognitive abnormalities, they are not sufficient alone to establish the developmental toxicity of a particular exposure in humans. The authors discuss the limitations of both and highlight that a valuable case study or clinical series is one that fully documents the agent, dose, rate, frequency, and stage in pregnancy of the exposures as well as a thorough characterization of the abnormalities in the affected children. Several examples related to teratogenic syndromes (eg, fetal alcohol syndrome, thalidomide embryopathy) and syndromes in which behavioral or cognitive phenotypes occur (eg, Fragile X syndrome, Prader-Willi syndrome) are presented and discussed.
Part 7 includes a range of topics related to specific neurotoxic syndromes resulting from exposure to methylmercury, cadmium, lead, alcohol, nicotine and tobacco, insecticides, PCBs, general anesthetics, drugs of abuse, and antiepileptic drugs. Chapter 35 provides a short overview of Minamata disease, which has become synonymous with methylmercury poisoning. Two exposure episodes are introduced, Minamata Bay, Japan (chronic exposure via seafood), and Iraq (acute exposure via contaminated grains). Understanding the role of mercury on neurodevelopmental processes is important as the fetus acts as a “mercury trap” accumulating mercury even higher than the maternal tissues. Rather than providing a comprehensive review of congenital mercury poisoning, the chapter focuses on one of the most characteristic effects of methylmercury on the developing brain—disruption of neuronal migration and neural cytoarchitecture. There is also discussion of the molecular impact of mercury on the cell adhesion molecules and on the cytoskeletal system of the nerve cells. In chapter 36, the authors address the current state of science with respect to the effects of cadmium on neurodevelopment. Several mechanisms are proposed, both indirect and direct, for how cadmium acts as a neurotoxicant, followed by a discussion of neurobehavioral outcomes in animals that demonstrate its neurotoxicity. The studies in humans seem to be equivocal with respect to the outcomes assessed; however, the weight of evidence suggests that measures should be taken to avoid or limit cadmium exposure during early life. Blood lead values at which medical attention is indicated have been reduced 5 times over the last 50 years as our knowledge of lead neurotoxicity and sophistication in testing children has increased. A safe level of lead that is free of toxic effects has yet to be established. Specific concerns vary with age and circumstances of the individual, with the major risk being toxicity to the CNS. Chapter 37 provides an overview of lead neurotoxicity in children, including effects on cognitive function, academic achievement, specific mental domains, and disturbances in mood and social behavior, followed by a discussion on the effects in animals. Although the impact of lead and neurodevelopment has been recognized for decades, this chapter provides critical updates with respect to approaches that have helped advance our understanding of the mechanisms involved. Alcohol-related fetal effects are a leading cause of mental delay and other forms of congenital brain injury that come at a great cost to the individual, the family, education, and health-care systems, as well as for society. In chapter 38, the authors discuss various aspects of fetal alcohol syndrome disorder, from maternal risk factors (ie, provocative and permissive factors) to diagnosis, challenges, and future directions. One of the greatest challenges is that the vast majority of children who have been prenatally exposed to alcohol do not present facial dysmorphology or physical impairments, but rather exhibit nonspecific complex mental, neurodevelopmental, behavioral, and cognitive disabilities that vary significantly in severity and spectrum. Various levels of prevention are discussed; however, appropriate polices need to be developed and enforced. Chapter 39 provides an overview of developmental neurotoxicity of nicotine and tobacco. The authors acknowledge that it is well recognized that maternal tobacco smoking during pregnancy is known to be related to perinatal mortality and morbidity, as well as persistent neurodevelopmental disorders. Developmental nicotine exposure affects basic processes of cell development and has deleterious effects on a variety of neurotransmitter systems that play a key role in cognition and behavior. In this chapter, which is an extension of the chapter presented in the first edition of this book, the authors present epidemiological data, animal studies evaluating the effects of nicotine exposure during development, and its impact on neuronal development, as well as the potential neurotoxicity of other compounds in tobacco (eg, carbon monoxide, hydrogen cyanide, benz-a-pyrene). It continues to be debated if nicotine replacement therapy is the best option for smoking cessation during pregnancy, and the authors conclude that the safest course is to discontinue all nicotine exposure during pregnancy. In chapter 40, the authors discuss the developmental neurobehavioral neurotoxicity of insecticides. Although insecticides primarily target the nervous system of insects, because of their low to moderate selectivity for insects, the potential exists for neurotoxic effects in off-target organisms, including humans. For humans, occupational exposure poses the greatest risk; however, the general population can be impacted via food and the environment. Because all 5 classes of insecticides (organochlorines, organophosphates, carbamates, pyrethroids, and neonicotinoids) readily cross physiological barriers, each is discussed with respect to their insecticidal versus off-target acute toxicity as well as developmental neurotoxicity. Organophosphates have the most complete body of evidence for developmental neurotoxicity, suggesting a broad window of vulnerability from early gestation to weaning. Ultimately, safer insecticides will have reduced persistence in the environment and greater selective toxicity for the target organism. Polychlorinated biphenyls are very stable and persistent compounds which contributes to their bioaccumulation (chapter 41). Because they are lipophilic, they can readily pass through the placenta to reach the fetus as well as accumulate in breast milk and affect offspring during lactation. Developmental exposure is associated with deficits in executive function, including cognitive flexibility, working memory, and inhibitory control (eg, substance abuse risk). Inhibitory control deficits have been observed across species (rats, monkeys, and humans). The authors discuss how PCBs alter psychostimulant behavioral pharmacology, the impact of PCB exposure on dopamine function, and potential sex differences in the developing brain following PCB exposure. Polychlorinated biphenyls are known endocrine disruptors, which may explain why males are often more sensitive. The evidence presented in this chapter lends support to the link between developmental PCB exposure, dopamine dysfunction, inhibitory control problems, and a propensity toward addiction later in life. However, epidemiological studies are needed to confirm whether these results translate to a human population. Although it is not confirmed in pediatric patients, nonclinical research has shown that general anesthesia during the period of rapid brain growth and development can induce robust apoptotic cell death (exact mechanisms are unclear), which may result in long-term deficits in cognitive function. Most general anesthetics act on NMDA or GABA receptors which may be the means by which they impact the developing brain. In chapter 42, the authors review the evidence of anesthetic-induced neurotoxicity from nonclinical studies, associations between developmental exposure to general anesthesia and adverse neurobehavioral outcomes in clinical studies, and potential therapeutic/protective compounds. Continuing investigations are necessary to better understand clinical relevance of nonclinical findings as well as to elucidate the underlying mechanisms of anesthetic-induced neurotoxicity. Chapter 43 focuses on neurobehavioral effects in the offspring of women who use drugs of abuse, including opiates, cocaine, marijuana, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA or ecstasy). The author discusses the challenges with delineating the impact of drug use relative to other potential contributing factors (eg, poor nutrition, home environment, poor prenatal care, etc). Each of the abovementioned drugs is addressed individually with respect to major neurobehavioral outcomes at specific life stages (ie, infants, children, and adolescents). Interestingly, there is preclinical and limited clinical evidence that both paternal and maternal exposure prior to mating can alter behavior in offspring possibly through epigenetic changes. Due to the common use of drugs in our society, it is important to understand the many factors that may lead to potential long-term consequences on the developing nervous system. In chapter 44, the developmental neurotoxicity of antiepileptic drugs is discussed. The authors address the clinical and nonclinical evidence pointing to neurobehavioral effects of prenatal exposure to anticonvulsants available prior to 1990 (eg, phenobarbital, phenytoin, carbamazepine, and valproic acid), as well as more recently available drugs such as lamotrigine and levetiracetam. In addition to the clinical evidence, there is discussion of the preclinical data investigating the potential mechanisms by which anticonvulsants impact key processes in brain development, including neurogenesis, migration, apoptosis, and synaptogenesis. Focusing on the weight of evidence from both clinical and nonclinical studies, it was concluded that not all antiepileptic drugs result in the same neurodevelopmental risk to the fetus. For example, valproic acid is a potent neurobehavioral teratogen with several identified outcomes on development; however, newer drugs (lamotrigine and levetiracetam) may present less risk, but still warrant continuing evaluation.
Part 8 consists of an overview of risk assessment with topics including current approaches to risk assessment for developmental neurotoxicity, animal/human concordance, PBPK models in risk assessment of developmental neurotoxicants, and application of quantitative dose–response data in risk assessment and the incorporation of high-throughput data. In chapter 45, the risk assessment paradigm (hazard identification, dose–response assessment, exposure assessment, and risk characterization) and its application to evaluating risk for DNT assessments is discussed. Along with the risk assessment paradigm, the authors point to US Environmental Protection Agency (EPA)-specific risk assessment guidelines (DNT, reproductive toxicity, neurotoxicity) that together provide a framework for DNT evaluations of environmental toxicants. Greater detail is provided around each of the major categories of risk assessment mentioned above as well as the end points and types of data that could be considered in the evaluation. The authors provide a thoughtful discussion around the pros and cons of both guideline-driven and nonguideline studies that serve as a useful reminder for anyone designing or conducting either type of study. Chapter 46 concisely summarizes the challenges with selecting the appropriate tests to characterize the effects of chemicals on the developing nervous system and further to determine whether the effects shown in an animal model are relevant to humans. Thyroid toxicants, methylmercury, inorganic lead, phenytoin, ethanol, and PCBs are cited as toxicants that result in similar DNT outcomes in both humans and animals. The authors describe common test batteries that are used to evaluate children for neurologic and cognitive deficits, followed by a detailed discussion of the DNT test approach in animals for regulatory purposes. An important concept covered in this chapter, as well as in chapter 45, is that the guideline studies are screens that may be broad in scope but have validated assays that are fit for purpose. Targeted testing may be necessary based on the chemical being investigated (eg, receptor binding, additional behavioral assays, and more specific neuropathology). In addition to the more traditional approaches, high-throughput screens such as a zebra fish model, in vitro assays using primary cells derived from humans, “human on a chip,” and “omic” technology, as well as PBPK modeling may help prioritize and refine future DNT evaluations. An overview of PBPK models and developmental neurotoxicity is provided in chapter 19, and chapter 47 focuses on how PBPK models can be applied in a DNT risk assessment (eg, reduce uncertainty factors). The chapter highlights how to construct, evaluate, and apply a PBPK model for the purpose of enhancing risk assessment of developmental neurotoxicants. The author highlights several considerations for characterizing confidence in PBPK models intended for specific end use in risk assessment. Ultimately, the author concludes that incorporating PBPK models into the risk assessment process will not only enhance the process but will also provide a framework for integrating new data on the mode of action, biomonitoring, and high-throughput screening. In the last chapter of this section (chapter 48), the author reiterates the basic principles of quantitative risk assessment (eg, identifying a point of departure, application of uncertainty factors, etc) and highlights several areas that need to be carefully considered before applying risk assessment (eg, problem formulation and planning and scoping). There is a thorough discussion of risk assessment fundamentals in the federal government with a specific focus on assessment of developmental toxicity risk and maternal effects. An additional section is devoted to defining an adverse effect. This issue becomes increasingly important as detection methods increase in sensitivity. For example, how are changes in biochemical pathways weighted against less sensitive traditional assays (eg, functional outcomes), and how does one define “adverse” and “not adverse” in those scenarios. There is also discussion around the applicability of high-throughput data in risk assessment; however, in the absence of a thorough understanding of underlying mechanisms, those data may be better suited for prioritization of chemicals for additional investigation.
The second edition of the Handbook of Developmental Neurotoxicology is a highly recommended reference for anyone working in the field of developmental neurotoxicity. As mentioned earlier, the chapters are succinct, with many of the key points summarized in tables. The individual sections flow very well, and several chapters complement others within the book. Considering that many of the chapters are updates to the first edition, general background information is not always included; therefore, the reader should have a foundation in the subject matter being discussed. For future editions of this book, it would be useful to have a more balanced perspective with additional contributions from industrial toxicologists. Several chapters highlight the challenges and/or limitations of conducting guideline-driven DNT studies, but few recommendations or suggestions are presented. There are often questions around selection of certain assays from the options presented in the guidelines, and scientists working in this area (eg, industry, contract research organizations, consultants, etc) would undoubtedly benefit from the experience and expertise of others as such studies are not only very costly and labor intensive but are also likely to have regulatory implications.