Nicotinamide benefits both mothers and pups in two contrasting mouse models of preeclampsia.

Preeclampsia (PE) complicates ∼5% of human pregnancies and is one of the leading causes of pregnancy-related maternal deaths. The only definitive treatment, induced delivery, invariably results in prematurity, and in severe early-onset cases may lead to fetal death. Many currently available antihypertensive drugs are teratogenic and therefore precluded from use. Nonteratogenic antihypertensives help control maternal blood pressure in PE, but results in preventing preterm delivery and correcting fetal growth restriction (FGR) that also occurs in PE have been disappointing. Here we show that dietary nicotinamide, a nonteratogenic amide of vitamin B3, improves the maternal condition, prolongs pregnancies, and prevents FGR in two contrasting mouse models of PE. The first is caused by endotheliosis due to excess levels in the mothers of a soluble form of the receptor for vascular endothelial growth factor (VEGF), which binds to and inactivates VEGF. The second is caused by genetic absence of Ankiryn-repeat-and-SOCS-box-containing-protein 4, a factor that contributes to the differentiation of trophoblast stem cells into the giant trophoblast cells necessary for embryo implantation in mice; its absence leads to impaired placental development. In both models, fetal production of ATP is impaired and FGR is observed. We show here that nicotinamide decreases blood pressure and endotheliosis in the mothers, probably by inhibiting ADP ribosyl cyclase (ADPRC), and prevents FGR, probably by normalizing fetal ATP synthesis via the nucleotide salvage pathway. Because nicotinamide benefits both dams and pups, it merits evaluation for preventing or treating PE in humans.

Association between in utero zidovudine exposure and nondefect adverse birth outcomes: analysis of prospectively collected data from the Antiretroviral Pregnancy Registry.

OBJECTIVE: To examine the association between nondefect adverse birth outcomes and in utero exposure to zidovudine (ZDV)-containing regimens versus non-ZDV antiretroviral (ARV) regimens. DESIGN: Analysis of prospectively-collected data. SETTING: Global. POPULATION: HIV-infected pregnant women prenatally exposed to antiretrovirals. METHODS: Estimation of prevalence of and risk for nondefect adverse birth outcomes among HIV-infected women. MAIN OUTCOME MEASURES: Prevalence of and risk for nondefect adverse birth outcomes. RESULTS: Among 12 780 singleton birth outcomes with in utero ZDV exposure, 96.1% were live births; 3.9% were spontaneous abortions, induced abortions or stillbirths. Among live births, 16.4% were low birthweight (LBW); 12.3% were premature. Among 1904 outcomes with in utero exposure to non-ZDV ARV regimens, 85.8% were live births; 14.2% were spontaneous abortions, induced abortions or stillbirths. Among live births, 14.1% were LBW; 12.4% were premature. Relative risk comparing exposure to ZDV-containing ARV regimens to non-ZDV ARV regimens for spontaneous abortions was 0.18 (95% confidence interval [95% CI] 0.14-0.22); induced abortions 0.28 (95% CI 0.22-0.36); stillbirths 0.76 (95% CI 0.51-1.12); premature births 1.00 (95% CI 0.87-1.15) and LBW 1.17 (95% CI 1.02-1.33). CONCLUSION: Prevalence of nondefect adverse birth outcomes is lower among outcomes with in utero ZDV exposure versus in utero non-ZDV ARV exposure. The risks for spontaneous and induced abortions were no different for ZDV-containing regimens versus non-ZDV ARV regimens. For premature births and stillbirths, there was no significant difference in risk between the two regimens. The risk of LBW was statistically significantly higher among ZDV-containing regimens versus non-ZDV ARV regimens. TWEETABLE ABSTRACT: ZDV-containing regimens do not increase the risk for nondefect adverse birth outcomes.

Role of the centers for education and research on therapeutics (CERTs) in pharmacovigilance and proper use of therapeutics.

According to the Institute of Medicine (IOM) Committee on the Assessment of the U.S. Drug Safety System, "The recent highly publicized controversies surrounding the safety of some drugs have contributed to a public perception that the drug safety system is in crisis. It seems fair to say that this perception has created an opportunity for a thorough evaluation of the U.S. drug safety system." The evaluation was focused on the U.S. Food and Drug Administration (FDA). To improve the FDA and its function in the public health system to improve therapeutics, it is critical to understand the contributions of other components.

Differential effects of two lots of aroclor 1254: congener-specific analysis and neurochemical end points.

Aroclor 1254 is a widely studied commercial polychlorinated biphenyl (PCB) mixture which, by definition, contains 54% chlorine by weight. Recent reports indicate substantial differences in the congener composition among Aroclor lots and hence their biologic effects. We designed the current study to compare the effects of two lots of Aroclor 1254 (lots 6024 and 124-191). We analyzed these two lots for PCB congeners, polychlorinated dibenzofurans (PCDFs), polychlorinated naphthalenes (PCNs), and polychlorinated dibenzodioxins (PCDDs). We used previously established techniques for analyzing intracellular Ca(2+) buffering and protein kinase C (PKC) translocation to test their biologic activity in neuronal preparations. PCB congener-specific analysis indicated that ortho and non-ortho congeners in these two lots varied in their percent contribution. Among all congeners, the percentages of non-ortho congeners (PCBs 77, 81, 126, and 169) were higher in lot 6024 (2.9% of total) than in lot 124-191 (0.02% of total). We detected no dioxins in these two lots (< 2 ppb). Although there are some differences in the congener composition, total PCNs were similar in both lots: 171 ppm in lot 6024 and 155 ppm in lot 124-191. However, total PCDFs were higher in lot 6024 (38.7 ppm) than in lot 124-191 (11.3 ppm). When we tested these two Aroclors on Ca(2+) buffering and PKC translocation in brain preparations, the effects were significantly different. Although lot 124-191 was more potent on PKC translocation than lot 6024, lot 6024 was slightly more active on Ca(2+) buffering than lot 124-191. These effects could not be attributed to the differences in the percentage of non-ortho congeners or PCDFs because they were inactive on these two parameters. The effects could not be attributed to PCNs because the levels were almost similar. The effects seen with two lots of Aroclor 1254 in neuronal cells were also not predicted based on the TCDD toxic equivalents (TEQs), although TEQs predicted the effects on ethoxyresorufin-O-deethylase (EROD) or methoxyresorufin-O-deethylase (MROD) activities. It is possible that the differential effects seen in neuronal cells could be caused by differences in the composition of ortho-congeners in these two mixtures, because PCBs with ortho-lateral substitutions can exhibit different activities on the selected neurochemical end points. Because of these differential effects with different lot numbers, the composition of Aroclor mixtures used in investigations should be disclosed.

Public health physicians: an endangered species.

BACKGROUND: Questions have arisen regarding the competency levels of the various professions within the public health sector, including those of physicians. Protection of the nation's health requires that physicians on the public health team be competent practitioners of both medicine and public health. Physicians practicing in this arena are required to possess a vast array of knowledge, skills, and attitudes to be effective contributors in the field. METHODS: Using focus groups of key informants in public health, the context of practice, inventory of required competencies, current competencies, and identified gaps in these competencies, measures to address the situation were identified and discussed. RESULTS: Recommendations from the focus groups include: use of distance-based learning, development of educational materials and programs, use of the American College of Preventive Medicine as a facilitator, improved remuneration, changes to the certification process, utilization of mentoring programs, introduction of new marketing strategies, use of professional publications, and increased governmental/agency support. Contributors to this endeavor are identified. CONCLUSIONS: While we strive to improve the physician workforce entering the field, creative strategies for continued lifelong learning are urgently needed to facilitate ongoing development of physicians in the current public health workforce. This situation presents a major research agenda for public health practice. Identification of the essential knowledge, skills, and attitudes for public health physicians is the first step toward narrowing gaps in required competencies.

Proactive safety surveillance.

Growth in health information systems presents opportunities to enhance postmarketing safety surveillance of medical products. Spontaneous suspected side effect reports provide the foundation, but we need to 'proactively' improve their quality and our strategies to seek signals. In our more familiar 'reactive' mode, we examine hypotheses from inquiries or publicity. Such responsive evaluations remain essential but may miss latent information on unsuspected risks. Efficient techniques to disclose hidden clusters and associations may emerge through adaptation of approaches from industrial quality control and other disciplines. Data-driven techniques like exploratory analysis, control charts, and time series modeling may help in sifting through accumulated data and in screening consecutive submissions to discern hints of new product hazards or of more specific understanding about previously identified potential side effects. We also need to cultivate non-spontaneous data for hypothesis generation as well as testing, the systematic epidemiologic evaluation of questions and concerns. This hypothesis testing function will assume greater importance if proactive safety surveillance methods yield larger numbers of putatively positive findings. Whether from spontaneous reports or other sources, signals that could have arisen by chance alone usually represent only clues to potential hazards until or unless they can be verified through independent studies.

Partnership for front-line success: a call for a national action agenda on workforce development.

Despite more than a decade of dialogue on the critical needs and challenges in public health workforce development, progress remains slow in implementing recommended actions. A life-long learning system for public health remains elusive. The Centers for Disease Control and Prevention and the Agency for Toxic Substances and Disease Registry in collaboration with other partners in federal, state, local agencies, associations and academia is preparing a national action agenda to address front-line preparedness. Four areas of convergence have emerged regarding: (1) the use of basic and crosscutting public health competencies to develop practice-focused curricula; (2) a framework for certification and credentialing; (3) the need to establish a strong science base for workforce issues; and (4) the acceleration of the use of technology-supported learning in public health.

Differential patterns of nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 mRNA and protein levels in developing regions of rat brain.

The present studies were undertaken to characterize the regional and temporal patterns of neurotrophin messenger RNA and protein levels for beta-nerve growth factor, brain-derived neurotrophic factor and neurotrophin-3 in the developing CNS. We have examined the levels of these neurotrophin messenger RNAs with ribonuclease protection assays and corresponding protein levels with enzyme-linked immunosorbent assays in the developing Long-Evans rat hippocampus, neocortex and cerebellum on postnatal days 1, 7, 14, 21, and 92. In addition, immunohistochemistry was used to localize the neurotrophins in these developing brain regions. Results indicated that in neocortex and hippocampus, messenger RNA for both nerve growth factor and brain-derived neurotrophic factor increased in an age-dependent manner, reaching a plateau by postnatal day 14. In the neocortex, nerve growth factor and brain-derived neurotrophic factor protein levels both peaked at postnatal day 14. In hippocampus, nerve growth factor protein peaked at postnatal day 7 while brain-derived neurotrophic factor peaked at postnatal day 14. In cerebellum, nerve growth factor messenger RNA levels were flat, while nerve growth factor protein peaked at postnatal day 7. Brain-derived neurotrophic factor messenger RNA increased in an age-dependent manner while the pattern for its protein levels was mixed. Neurotrophin-3 messeger RNA levels increased in an age-dependent manner in hippocampus, peaked at postnatal day14 in cerebellum, and no changes occurred in neocortex. Neurotrophin-3 protein was at its peak at postnatal day 1 and thereafter decreased at other postnatal days in all three brain regions. Results of neurotrophin immunohistochemistry often paralleled and complemented enzyme-linked immunosorbent assay data, demonstrating specific cell groups containing neurotrophin proteins in these regions. Within each region, patterns with regard to messenger RNA and respective protein levels for each neurotrophin were unique. No consistent relationship between patterns of neurotrophin messenger RNAs and their cognate proteins was observed between regions. The different regional patterns for neurotrophin messengerRNA and protein levels in each brain region indicate that messenger RNA studies of neurotrophin messenger RNA must be augmented by protein determination to fully characterize spatial and temporal neurotrophin distribution.

Overview of neurotoxicology.

Environmental exposure to chemicals such as lead, mercury, organic solvents, pesticides, as well as naturally occurring compounds have neurotoxic effects. This unit is an overview of the structure and function of the nervous system, including a discussion of critical issues in defining neurotoxic effects and neurotoxicological risk assessment.

Neurochemical effects of environmental chemicals: in vitro and in vivo correlations on second messenger pathways.

Polychlorinated biphenyls (PCBs) are persistent, bioaccumulative, toxic, and widely distributed environmental chemicals. There is now both epidemiological and experimental evidence that PCBs cause cognitive deficits; however, the underlying cellular or molecular mechanism(s) is not known. We have hypothesized that altered signal transduction/second messenger homeostasis by PCBs may be associated with these effects since second messengers in signal transduction pathways, such as calcium, inositol phosphates (IP), and protein kinase C (PKC), play key roles in neuronal development and their function. In vitro studies using cerebellar granule neurons and isolated organelle preparations indicate that ortho-PCBs increase intracellular free Ca2+ levels by inhibiting microsomal and mitochondrial Ca2+ buffering and the Ca2+ extrusion process. Ortho-PCBs also increase agonist-stimulated IP accumulation and cause PKC translocation at low micromolar concentrations where no cytotoxicity is observed. On the other hand, non-ortho-PCBs are not effective in altering these events. Further SAR studies indicate that congeners with chlorine substitutions favoring non-coplanarity are active in vitro, while congeners favoring coplanarity are relatively inactive. Subsequent in vivo studies have shown that repeated exposure to a PCB mixture, Aroclor 1254, increases PKC translocation and decreases Ca2+ buffering in the brain, similar to in vitro studies. These changes in vivo are associated with elevated levels of non-coplanar ortho-PCB congeners at levels equivalent to 40-50 microM in brain, the concentrations that significantly inhibited second messenger systems in neuronal cultures in vitro. Current research is focusing on PCB-induced alterations in second messenger systems following developmental exposure.

New horizons: future directions in neurotoxicology.

Neurotoxicology is a relatively young discipline that has undergone significant growth during the last 25 years. During the late 1970s and 1980s, numerous national and international conferences and meetings were devoted to the topic of neurotoxicology, the formation of societies or specialty sections related to neurotoxicology, and the establishment of two independent peer-reviewed journals devoted to neurotoxicology. This decade was also associated with a rapid increase in our knowledge of chemical effects on the structure and function of the nervous system. During the 1990s, regulatory agencies such as the U.S. Environmental Protection Agency accepted neurotoxicology as a crucial end point and neurotoxicity testing and risk assessment guidelines were published. Neurotoxicology has also been accepted at the international level as evidenced by environmental criteria documents published by the International Programme on Chemical Safety and testing guidelines by the Organization of Economic Cooperation and Development. In recent years, there has been increased concern that the etiology of some neurodegenerative diseases may be associated with exposure to neurotoxic agents and that subpopulations of humans such as children and the elderly may be differentially sensitive to neurotoxic exposure. In the future, mechanistic information derived from basic research will be used in the identification and characterization of chemicals with neurotoxic potential.

Neurotoxicology risk assessment guidelines: developmental neurotoxicology.

EPA's Neurotoxicity Risk Assessment Guidelines were recently published in final form in the Federal Register (1998). This document was developed over a period of nearly ten years and is intended to establish operating principles used in the evaluation of data for neurotoxicity risk assessment. The guidelines contain a number of assumptions and definitions of key concepts, as well as guidance as to the evaluation of various behavioral and structural changes produced by chemical exposure in humans and animals. With regard to developmental neurotoxicity, risk assessors should be aware that chemical-induced neurotoxicity in adults may not always be a good predictor of developmental neurotoxicity. Adverse effects on the developing nervous system can occur prior to conception up to the time of sexual maturity, depend on the time of exposure relative to a critical state of nervous system development, can be seen at any time during the lifespan of the organism, may lead to delayed onset or latent effects, and may elicit compensatory mechanisms that obscure underlying neurotoxicity. Adverse effects include persistent alterations in function or structure of the nervous system or a change in the time or appearance of any endpoint. Relative to neurotoxicity in adult animals, there are several special concerns in hazard characterization of developmental studies, including maternal toxicity, the use of the litter as the statistical unit, and time of exposure relative to the ontogeny of various structural or functional endpoints. Dose-response evaluation of data from developmental studies is similar to that for adults, although a safety factor of 10 may be applied to protect children's health. The guidelines also note that exposure patterns of children differ from those of adults resulting in a greater intake of chemicals on a per body weight basis. The guidelines note several research needs, including more information on mechanisms of developmental neurotoxicity, mechanistically based dose-response models, impact of early exposure to chemicals on late-onset disease, studies on threshold, and experiments on potential interactions between chemicals in mixtures.

The role of developmental neurotoxicology studies in risk assessment.

A number of questions have been raised about the use of the US Environmental Protection Agency's Developmental Neurotoxicity Testing Guideline (DNTG) in the hazard identification of chemicals. The applicability and sensitivity of animal tests in the DNTG relative to human developmental neurotoxicity have recently been questioned. In a workshop held in 1989, participants compared the effects of several known developmental neurotoxicants in humans and animal models and concluded that the DNTG would have detected known human developmental neurotoxicants. They also concluded that although procedural differences may differ in the testing of humans and animals, the neurobiologic functions (ie, autonomic, sensory, motor, and cognitive) affected by chemical exposure were similar. In cases where the DNTG has been compared with other measures of reproductive and developmental toxicity, the DNTG has been relatively sensitive and specific. To date, DNTGs have been required 12 times, for 9 pesticides and 3 solvents. The sensitivity of the measures in the DNTG relative to other measures of developmental and adult toxicity supports the continued use of the DNTG in risk assessment.

Extracellular calcium is required for the polychlorinated biphenyl-induced increase of intracellular free calcium levels in cerebellar granule cell culture.

Recent studies from the laboratory indicate that polychlorinated biphenyl (PCB) congeners can alter signal transduction and calcium homeostasis in neuronal preparations. These effects were more pronounced for the ortho-substituted, non-coplanar congeners, although the mechanisms underlying these effects are not clear. In the present study the time-course and concentration-dependent effects of coplanar and non-coplanar PCBs on intracellular free calcium concentration ([Ca2+]i) in cerebellar granule cell cultures were compared using the fluorescent probe fura-2. The ortho-substituted congeners 2,2'-dichlorobiphenyl (DCB) and 2,2',4,6,6'-pentachlorobiphenyl (PeCB) caused a gradual increase of [Ca2+]i while the non-ortho-substituted congeners 4,4'-DCB and 3,3',4,4',5-PeCB had no effect. The increase of [Ca2+]i produced by 2,2'-DCB was time- and concentration-dependent. Further studies examined possible mechanisms for this rise in [Ca2+]i. In contrast to the muscarinic agonist carbachol, the effects of 2,2'-DCB on [Ca2+]i were not blocked by thapsigargin and required the presence of extracellular calcium. The effects of ortho-substituted PCBs may depend on their ability to inhibit calcium sequestration as 2,2'-DCB significantly inhibited 45Ca2+-uptake by microsomes and mitochondria while 3,3',4,4',5-PeCB had no effect. In addition, 2,2'-DCB significantly increased the binding of [3H]inositol 1,4,5-trisphosphate to receptors on cerebellar microsomes, suggesting another possible mechanism by which ortho-substituted PCBs can mobilize [Ca2+]i. These results show that PCBs increase [Ca2+]i in vitro via a mechanism that requires extracelluar calcium, and support previous structure-activity studies indicating that ortho-substituted PCBs are more potent than non-ortho-substituted PCBs.

Understanding the NIH review process: a brief guide to writing grant proposals in neurotoxicology.

During the past two years, the National Institutes of Health have made significant changes in the review process for investigator-initiated research grant applications in neurotoxicology. First, study sections that formerly dealt with toxicology and alcohol, respectively, have been merged. Neurotoxicology grant applications are now reviewed by ALTX-3, a study section in which the majority of members have expertise in the neuronal, biochemical or behavioral effects of alcohol, but usually not other neurotoxicants. Second, the NIH has instituted new review criteria, in which significance, approach, innovation, investigator expertise, and research environment must all be explicitly addressed by the reviews. In this article, past and present members of the ALTX-3 study section describe the NIH review process, with emphasis on how neurotoxicology applications are handled, and provide guidelines for preparing competitive applications.

The neurotoxicity of polychlorinated biphenyls.

Like dioxin, some polychlorinated biphenyl (PCB) congeners produce toxicity by binding to an aryl hydrocarbon (Ah) receptor. Other PCB congeners that have little or no activity at the Ah receptor have been shown to accumulate in the brain following in vivo exposure and decrease dopamine content. Subsequent research has found that non-dioxin-like PCBs also interfere with calcium homeostatic mechanisms and intracellular second messenger systems in vitro in neuronal cultures and brain subcellular fractions. The biological significance of these effects of PCBs in nervous system preparations is not known, although a number of calcium-dependent processes are important for nervous system function and development. Structure-activity relationship (SAR) studies based on measures of PCB-induced alterations in protein kinase C (PKC) translocation and Ca2+-buffering indicate that congeners with chlorine substitutions at the ortho-position are active in vitro, while non-ortho congeners are relatively inactive. Subsequent research has found that chloride substitution patterns that favor non-co-planarity are associated with activity in nervous system preparations. Recent in vivo studies in adults have shown that repeated exposure to a PCB mixture Aroclor 1254 increases translocation of PKC and decreases Ca2+-buffering in the brain. Increased levels of ortho-substituted non-coplanar PCB congeners were observed in the brains of Aroclor 1254-treated animals relative to vehicle controls. Current research is focusing on the possibility that PCB-induced alterations in calcium homeostasis and intracellular second messengers may be related to the developmental neurotoxicity of PCBs.

Gestational exposure to methylmercury alters the developmental pattern of trk-like immunoreactivity in the rat brain and results in cortical dysmorphology.

Nerve growth factor signal transduction mediated through the trk receptor has been implicated in neuronal growth, differentiation, and survival. In this study, we examined the effects of gestational exposure to the developmental neurotoxicant methylmercury (CH3Hg) on the ontogeny of trk-immunoreactivity (IR). Long-Evans dams were dosed on gestational days 6-15 (p.o.) with 0, 1, or 2 mg/kg CH3Hg dissolved in saline. Pups were sacrificed and perfused with buffered paraformaldehyde on postnatal days (PND) 1, 4, 10, 21 and 85. The brains were sectioned sagitally, Nissl-stained or stained immunohistochemically for trk receptors or glial fibrillary acidic protein (GFAP), and examined throughout the medial to lateral extent of the brain. The greatest density of IR in neural cell bodies was seen in the olfactory bulb, hippocampus, cerebral, and cerebellar cortex, striatum, septum, nucleus basalis, inferior colliculus, pons, and brain stem nuclei. trk IR was not limited to nerve cell bodies, with prominent axonal and dendritic staining in the brainstem, neocortex, hippocampus, cerebellum, and olfactory tract. The regional pattern of trk IR varied in an age-dependent manner. In controls, trk-like IR appeared to peak in most regions between PND4-10 and decreased dramatically after PND21. This age-related difference in trk IR was supported by western blot analysis of PND10 and adult neocortex. This reduced and more adult-like pattern of trk IR was apparent on PND21 with some persistent trk-like IR in the olfactory bulb, hippocampus, neocortex, cerebellum and basal forebrain. In contrast to the normal regional patterns of trk IR, CH3Hg produced a dose-related decrease in trk-like IR in the absence of overt maternal toxicity or neonatal toxicity. CH3Hg-induced decreases in trk-like IR were especially apparent during the early postnatal period when trk IR was the greatest. The effects of CH3Hg exposure were restricted regionally, with the largest decrease in trk-like IR apparent in cortical regions, basal forebrain nuclei, and brain stem nuclei. Subsequent to the effects of CH3Hg on cortical trk-like IR were alterations in the development of cortical laminae on PND10 and 21 of neocortex. These alterations were characterized by quantifiable decreases in cell density, cell size and the widths of the layers of posterior neocortex. Not all of the CH3Hg-induced effects were characterized by decreased trk-like IR. Robust increases in trk IR in glial cells in the corpus callosum and brain stem were observed coincident with increased GFAP IR in cells of similar morphology. The present results localize the cellular and regional ontogeny of trk and suggest that developmental exposure to CH3Hg alters the normal ontogeny of this trophic factor receptor which may be associated with the developmental neurotoxicity of this chemical.

Developmental neurotoxicology of endocrine disruptors and pesticides: identification of information gaps and research needs.

There is increasing evidence that some environmental chemicals can interrupt neurodevelopmental processes during critical periods of development, resulting in effects on sensory, motor, and cognitive function. It is now generally accepted that developing organisms are differentially sensitive to chemical exposure because of toxicokinetic and/or toxicodynamic factors. Regulatory mechanisms have been implemented to protect humans from over- or inappropriate exposures to environmental chemicals. Current regulatory practices, however, may be insufficient because of the possibility that some environmental chemicals interfere with endocrine function at key periods of neurodevelopment. In addition, a recent National Research Council (NRC) report on pesticide contamination in the diets of infants and children concluded that current regulatory practices may not sufficiently protect infants and children from the risk of pesticide exposure. The NRC report indicates that regulatory agencies might underestimate the actual exposure of infants and children to pesticides and rely too heavily on data from adults in the risk assessment of pesticides. Consideration of endocrine-disrupting chemicals and the differential susceptibility of infants and children has led to identification of a number of information gaps and research needs that should be addressed in order to improve future risk assessments for these chemicals.