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11.9: Case Study Memory Conclusion and Chapter Summary - Biology

11.9: Case Study Memory Conclusion and Chapter Summary - Biology



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Case Study Conclusion: Fading Memory

Figure (PageIndex{1}) illustrates some of the molecular and cellular changes that occur in Alzheimer’s disease (AD), which Rosa was diagnosed with at the beginning of this chapter, after experiencing memory problems and other changes in her cognitive functioning, mood, and personality. These abnormal changes in the brain include the development of amyloid plaques between brain cells and neurofibrillary tangles inside of neurons. These hallmark characteristics of AD are associated with the loss of synapses between neurons, and ultimately the death of neurons.

After reading this chapter, you should have a good appreciation for the importance of keeping neurons alive and communicating with each other at synapses. The nervous system coordinates all of the body’s voluntary and involuntary activities. It interprets information from the outside world through sensory systems and makes appropriate responses through the motor system, through communication between the PNS and CNS. The brain directs the rest of the nervous system and controls everything from basic vital functions such as heart rate and breathing to high-level functions such as problem-solving and abstract thought. The nervous system is able to perform these important functions by generating action potentials in neurons in response to stimulation and sending messages between cells at synapses, typically using chemical neurotransmitter molecules. When neurons are not functioning properly, lose their synapses, or die, they cannot carry out the signaling that is essential for the proper functioning of the nervous system.

AD is a progressive neurodegenerative disease, meaning that the damage to the brain becomes more extensive as time goes on. Figure (PageIndex{2}) illustrates how the damage progresses from before AD is diagnosed (preclinical AD), to mild and moderate AD, and finally to severe AD.

You can see that the damage starts in a relatively small location towards the bottom of the brain. One of the earliest brain areas to be affected by AD is the hippocampus. The hippocampus is important for learning and memory. This explains why many of Rosa’s symptoms of mild AD involve deficits in memory, such as trouble remembering where she placed objects, recent conversations, and appointments.

As AD progresses, more of the brain is affected, including areas involved in emotional regulation, social behavior, planning, language, spatial navigation, and higher-level thought. Rosa is beginning to show signs of problems in these areas, including irritability, lashing out at family members, getting lost in her neighborhood, problems finding the right words, putting objects in unusual locations, and difficulty in managing her finances. You can see that as AD progresses, damage spreads further across the cerebrum, which you now know controls conscious functions such as reasoning, language, and interpretation of sensory stimuli. You can also see how the frontal lobe, which controls executive functions such as planning, self-control, and abstract thought, becomes increasingly damaged.

Increasing damage to the brain causes corresponding deficits in functioning. In moderate AD, patients have increased memory, language, and cognitive deficits compared to mild AD. They may not recognize their own family members, and may wander and get lost, engage in inappropriate behaviors, become easily agitated, and have trouble carrying out daily activities such as dressing. In severe AD, much of the brain is affected. Patients usually cannot recognize family members or communicate and are fully dependent on others for their care. They begin to lose the ability to control their basic functions, such as bladder and bowel control and proper swallowing. Eventually, AD causes death, usually as a result of this loss of basic functions.

For now, Rosa only has mild AD is still able to function relatively well with care from her family. The medication her doctor gave her has helped improve some of her symptoms. It is a cholinesterase inhibitor, which blocks an enzyme that normally degrades the neurotransmitter acetylcholine. With more of the neurotransmitter available, more of it can bind to neurotransmitter receptors on postsynaptic cells. Therefore, this drug acts as an agonist for acetylcholine, which enhances communication between neurons in Rosa’s brain. This increase in neuronal communication can help restore some of the functions lost in early Alzheimer’s disease and may slow the progression of symptoms.

But medication such as this is only a short-term measure and does not halt the progression of the underlying disease. Ideally, the damaged or dead neurons would be replaced by new, functioning neurons. Why does this not happen automatically in the body? As you have learned, neurogenesis is very limited in adult humans, so once neurons in the brain die, they are not normally replaced to any significant extent. However, scientists are studying the ways in which neurogenesis might be able to be increased in cases of disease or injury to the brain. Also, they are investigating the possibility of using stem cell transplants to replace damaged or dead neurons with new neurons. But this research is in very early stages and is not currently a treatment for AD.

One promising area of research is in the development of methods to allow earlier detection and treatment of AD, given that the changes in the brain may actually start 10 to 20 years before the diagnosis of AD. For example, a radiolabeled chemical called Pittsburgh Compound B (PiB) binds to amyloid plaques in the brain and in the future may be used in conjunction with brain imaging techniques to detect early signs of AD. Scientists are also looking for biomarkers in bodily fluids such as blood and cerebrospinal fluid that might indicate the presence of AD before symptoms appear. Finally, researchers are also investigating possible early and subtle symptoms, such as changes in how people move or a loss of smell, to see whether they can be used to identify people who will go on to develop AD. This research is in the early stages, but the hope is that patients can be identified earlier to provide earlier and possibly more effective treatment and to allow families more time to plan.

Scientists are also still trying to fully understand the causes of AD, which affects more than 5 million Americans. Some genetic mutations have been identified that play a role, but environmental factors also appear to be important. With more research into the causes and mechanisms of AD, hopefully, a cure can be found, and people like Rosa can live a longer and better life.

Chapter Summary

In this chapter, you learned about the human nervous system. Specifically, you learned that:

  • The nervous system is the organ system that coordinates all of the body’s voluntary and involuntary actions by transmitting signals to and from different parts of the body. It has two major divisions, the central nervous system (CNS) and the peripheral nervous system (PNS).
  • The CNS includes the brain and spinal cord.
  • The PNS consists mainly of nerves that connect the CNS with the rest of the body. It has two major divisions: the somatic nervous system and the autonomic nervous system. The somatic system controls activities that are under voluntary control. The autonomic system controls activities that are involuntary.
  • The autonomic nervous system is further divided into the sympathetic division, which controls the fight-or-flight response; the parasympathetic division, which controls most routine involuntary responses; and the enteric division, which provides local control for digestive processes.
  • Signals sent by the nervous system are electrical signals called nerve impulses. They are transmitted by special, electrically excitable cells called neurons, which are one of two major types of cells in the nervous system.
  • Glial cells are the other major type of nervous system cells. There are many types of glial cells, and they have many specific functions. In general, glial cells function to support, protect, and nourish neurons.
  • The main parts of a neuron include the cell body, dendrites, and axon. The cell body contains the nucleus. Dendrites receive nerve impulses from other cells, and the axon transmits nerve impulses to other cells at axon terminals. A synapse is a complex membrane junction at the end of an axon terminal that transmits signals to another cell.
  • Axons are often wrapped in an electrically-insulating myelin sheath, which is produced by glial cells. Electrical impulses called action potentials occur at gaps in the myelin sheath, called nodes of Ranvier, which speeds the conduction of nerve impulses down the axon.
  • Neurogenesis, or the formation of new neurons by cell division, may occur in a mature human brain but only to a limited extent.
  • The nervous tissue in the brain and spinal cord consists of gray matter, which contains mainly the cell bodies of neurons; and white matter, which contains mainly myelinated axons of neurons. Nerves of the peripheral nervous system consist of long bundles of myelinated axons that extend throughout the body.
  • There are hundreds of types of neurons in the human nervous system, but many can be classified on the basis of the direction in which they carry nerve impulses. Sensory neurons carry nerve impulses away from the body and toward the central nervous system, motor neurons carry them away from the central nervous system and toward the body, and interneurons often carry them between sensory and motor neurons.
  • A nerve impulse is an electrical phenomenon that occurs because of a difference in electrical charge across the plasma membrane of a neuron.
  • The sodium-potassium pump maintains an electrical gradient across the plasma membrane of a neuron when it is not actively transmitting a nerve impulse. This gradient is called the resting potential of the neuron.
  • An action potential is a sudden reversal of the electrical gradient across the plasma membrane of a resting neuron. It begins when the neuron receives a chemical signal from another cell or some other type of stimulus. The action potential travels rapidly down the neuron’s axon as an electric current.
  • A nerve impulse is transmitted to another cell at either an electrical or a chemical synapse. At a chemical synapse, neurotransmitter chemicals are released from the presynaptic cell into the synaptic cleft between cells. The chemicals travel across the cleft to the postsynaptic cell and bind to receptors embedded in its membrane.
  • There are many different types of neurotransmitters. Their effects on the postsynaptic cell generally depend on the type of receptor they bind to. The effects may be excitatory, inhibitory, or modulatory in more complex ways. Both physical and mental disorders may occur if there are problems with neurotransmitters or their receptors.
  • The CNS includes the brain and spinal cord. It is physically protected by bones, meninges, and cerebrospinal fluid. It is chemically protected by the blood-brain barrier.
  • The brain is the control center of the nervous system and of the entire organism. The brain uses a relatively large proportion of the body’s energy, primarily in the form of glucose.
  • The brain is divided into three major parts, each with different functions: brain stem, cerebellum, and cerebrum. The cerebrum is further divided into left and right hemispheres. Each hemisphere has four lobes: frontal, parietal, temporal, and occipital. Each lobe is associated with specific senses or other functions.
  • The cerebrum has a thin outer layer called the cerebral cortex. Its many folds give it a large surface area. This is where most information processing takes place.
  • Inner structures of the brain include the hypothalamus, which controls the endocrine system via the pituitary gland; and the thalamus, which has several involuntary functions.
  • The spinal cord is a tubular bundle of nervous tissues that extends from the head down the middle of the back to the pelvis. It functions mainly to connect the brain with the PNS. It also controls certain rapid responses called reflexes without input from the brain.
  • A spinal cord injury may lead to paralysis (loss of sensation and movement) of the body below the level of the injury because nerve impulses can no longer travel up and down the spinal cord beyond that point.
  • The PNS consists of all the nervous tissue that lies outside of the CNS. Its main function is to connect the CNS to the rest of the organism.
  • The tissues that make up the PNS are nerves and ganglia. Ganglia act as relay points for messages that are transmitted through nerves. Nerves are classified as sensory, motor, or a mix of the two.
  • The PNS is not as well protected physically or chemically as the CNS, so it is more prone to injury and disease. PNS problems include injury from diabetes, shingles, and heavy metal poisoning. Two disorders of the PNS are Guillain-Barre syndrome and Charcot-Marie-Tooth disease.
  • The human body has two major types of senses, special senses, and general senses. Special senses have specialized sense organs and include vision (eyes), hearing (ears), balance (ears), taste (tongue), and smell (nasal passages). General senses are all associated with touch and lack special sense organs. Touch receptors are found throughout the body but particularly in the skin.
  • All senses depend on sensory receptor cells to detect sensory stimuli and transform them into nerve impulses. Types of sensory receptors include mechanoreceptors (mechanical forces), thermoreceptors (temperature), nociceptors (pain), photoreceptors (light), and chemoreceptors (chemicals).
  • Touch includes the ability to sense pressure, vibration, temperature, pain, and other tactile stimuli. The skin includes several different types of touch receptor cells.
  • Vision is the ability to sense light and see. The eye is the special sensory organ that collects and focuses light, forms images, and changes them to nerve impulses. Optic nerves send information from the eyes to the brain, which processes the visual information and “tells” us what we are seeing.
  • Common vision problems include myopia (nearsightedness), hyperopia (farsightedness), and presbyopia (age-related decline in close vision).
  • Hearing is the ability to sense sound waves, and the ear is the organ that senses sound. It changes sound waves to vibrations that trigger nerve impulses, which travel to the brain through the auditory nerve. The brain processes the information and “tells” us what we are hearing.
  • The ear is also the organ that is responsible for the sense of balance, which is the ability to sense and maintain an appropriate body position. The ears send impulses on head position to the brain, which sends messages to skeletal muscle via the peripheral nervous system. The muscles respond by contracting to maintain balance.
  • Taste and smell are both abilities to sense chemicals. Taste receptors in taste buds on the tongue sense chemicals in food and olfactory receptors in the nasal passages sense chemicals in the air. The sense of smell contributes significantly to the sense of taste.
  • Psychoactive drugs are substances that change the function of the brain and result in alterations of mood, thinking, perception, and/or behavior. They include prescription medications such as opioid painkillers, legal substances such as nicotine and alcohol, and illegal drugs such as LSD and heroin.
  • Psychoactive drugs are divided into different classes according to their pharmacological effects. They include stimulants, depressants, anxiolytics, euphoriants, hallucinogens, and empathogens. Many psychoactive drugs have multiple effects so they may be placed in more than one class.
  • Psychoactive drugs generally produce their effects by affecting brain chemistry. Generally, they act either as agonists, which enhance the activity of particular neurotransmitters; or as antagonists, which decrease the activity of particular neurotransmitters.
  • Psychoactive drugs are used for various purposes, including medical, ritual, and recreational purposes.
  • Misuse of psychoactive drugs may lead to addiction, which is the compulsive use of a drug despite negative consequences. Sustained use of an addictive drug may produce physical or psychological dependence on the drug. Rehabilitation typically involves psychotherapy and sometimes the temporary use of other psychoactive drugs.

In addition to the nervous system, there is another system of the body that is important for coordinating and regulating many different functions – the endocrine system. You will learn about the endocrine system in the next chapter.

Chapter Summary Review

  1. Imagine that you decide to make a movement. To carry out this decision, a neuron in the cerebral cortex of your brain (neuron A) fires a nerve impulse that is sent to a neuron in your spinal cord (neuron B). Neuron B then sends the signal to a muscle cell, causing it to contract, resulting in movement. Answer the following questions about this pathway.
    1. Which part of the brain is neuron A located in — the cerebellum, cerebrum, or brain stem? Explain how you know.
    2. The cell body of neuron A is located in a lobe of the brain that is involved in abstract thought, problem-solving and planning. Which lobe is this?
    3. Part of neuron A travels all the way down to the spinal cord to meet neuron B. Which part of neuron A travels to the spinal cord?
    4. Neuron A forms a chemical synapse with neuron B in the spinal cord. How is the signal from neuron A transmitted to neuron B?
    5. Is neuron A in the central nervous system (CNS) or peripheral nervous system (PNS)?
    6. The axon of neuron B travels in a nerve to a skeletal muscle cell. Is the nerve part of the CNS or PNS? Is this an afferent nerve or an efferent nerve?
    7. What part of the PNS is involved in this pathway — the autonomic nervous system or the somatic nervous system? Explain your answer.
  2. What are the differences between a neurotransmitter receptor and a sensory receptor?
  3. Which part of a postsynaptic neuron typically receives the signals from a presynaptic neuron?
    1. The axon terminal
    2. The nodes of Ranvier
    3. The dendrites
    4. The cell body
  4. True or False. Glial cells produce action potentials.
  5. True or False. The spinal cord consists of white matter only.
  6. True or False. Axons may be more than a meter long in adult humans.
  7. If a person has a stroke and as a result has trouble using language correctly, which hemisphere of their brain was most likely damaged? Explain your answer.
  8. The right side of the brain generally controls the which side of the body?
    1. right side
    2. left side
    3. head region
    4. trunk and leg regions
  9. Electrical gradients are responsible for the resting potential and action potential in neurons. Answer the following questions about the electrical characteristics of neurons.
    1. Define what an electrical gradient is, in the context of a cell.
    2. What is responsible for maintaining the electrical gradient that results in the resting potential?
    3. Compare and contrast the resting potential and the action potential.
    4. Where along a myelinated axon does the action potential occur? Why does it happen here?
  10. What does it mean that the action potential is “all-or-none?”
  11. What determines whether a neurotransmitter has an excitatory or inhibitory effect? Choose the best answer.
    1. The neurotransmitter itself
    2. The specific receptor for the neurotransmitter on the postsynaptic cell
    3. The number of synaptic vesicles in the axon terminal
    4. Whether it is in a sensory neuron or a motor neuron
  12. Compare and contrast Schwann cells and oligodendrocytes.
  13. True or False. The cerebellum makes up most of the brain and is divided into four lobes.
  14. True or False. The hypothalamus is part of the brain.
  15. Which lobe of the brain processes touch information?
    1. Parietal
    2. Occipital
    3. Cochlea
    4. Temporal
  16. Information about sounds is mainly sent to which lobe of the brain?
    1. Parietal
    2. Occipital
    3. Cochlea
    4. Temporal
  17. Rods and cones in the retina are:
    1. Mechanoreceptors
    2. Nociceptors
    3. Photoreceptors
    4. Chemoreceptors
  18. For the senses of smell and hearing, name their respective sensory receptor cells, what type of receptor cells they are, and what stimuli they detect.
  19. True or False. Sensory information such as smell, taste, and sound, are carried to the CNS by cranial nerves.
  20. True or False. The parasympathetic nervous system is a division of the central nervous system.

Nutritional Genomics: Discovering the Path to Personalized Nutrition


Though still in its infancy, nutritional genomics, or "nutrigenomics," has revealed much about the complex interactions between diet and genes. But it is in its potential applications that nutrigenomics promises to revolutionize the ways we manage human health and combat disease in the years ahead. Great progress already has been made in modeling "personalized" nutrition for optimal health and longevity as well as in genotype-based dietary interventions for the prevention, mitigation, or possible cure of a variety of chronic diseases and some types of cancer.

Topics covered include:
* Nutrients and gene expression
* The role of metabolomics in individualized health
* Molecular mechanisms of longevity regulation and calorie restriction
* Green tea polyphenols and soy peptides in cancer prevention
* Maternal nutrition and fetal gene expression
* Genetic susceptibility to heterocyclic amines from cooked foods
* Bioinformatics and biocomputation in nutrigenomics
* The pursuit of optimal diets

Written by an all-star team of experts from around the globe, this volume provides an integrated overview of the cutting-edge field of nutritional genomics. The authors and editors lead an in-depth discussion of the fundamental principles and scientific methodologies that serve as the foundation for nutritional genomics and explore important recent advances in an array of related disciplines. Each self-contained chapter builds upon its predecessor, leading the reader seamlessly from basic principles to more complex scientific findings and experimental designs. Scientific chapters are carefully balanced with those addressing the social, ethical, regulatory, and commercial implications of nutrigenomics.

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1. An Introduction and Overview of Nutritional Genomics: Application to Type 2 Diabetes and International Nutrigenomics (Jim Kaput).

Understanding T2DM: the current view of T2DM and treatment options.

Understanding T2DM: begin before conception.

Understanding T2DM: genetic complexity.

Understanding T2DM: QTLs in humans.

Understanding T2DM: from birth onward.

Understanding T2DM: metabolomics.

Understanding T2DM: environmental influences.

Understanding T2DM: environment is more than diet.

Understanding T2DM: data acquisition and analyses.

Bioinformatics and biocomputation.

Converting science into practice.

Research ethics and genetic privacy.

Public and international policies.

2. The Pursuit of Optimal Diets: A Progress Report (Walter C. Willett).

2.2 Considerations in defining an optimal diet.

2.3 Dietary fat and specific fatty acids.

2.7 Calcium and dairy products.

2.8 Salt and processed meats.

2.10 Vitamin and mineral supplements.

2.11 The potential impact of optimal diet and lifestyle changes.

3. Gene - Environment Interactions: Defining the Playfield (Jose M. Ordovas and Dolores Corella).

3.2 How to detect genetic variability?.

3.5 Gene-environment interactions: focus on diet.

3.6 Common genetic variants and their interaction with dietary factors.

3.7 Gene X Microorganisms interactions.

3.8 The microbiome (microbiota).

4. Metabolomics: Bringing Nutrigenomics to Practice in Individualized Health Asssessment (J. Bruce German, Cora J. Dillard, S. Luke Hillyard, Matthew C. Lange, Jennifer T. Smilowitz, Robert E. Ward, and Angela M. Zivkovic).

4.2 Opportunities for foods and health.

4.4 The future of metabolomics.

4.6 Metabolome assembly and annotation.

4.7 Bioinformatics: knowledge management from genomics and metabolomics to health assessment.

5. Genetic and molecular buffering of phenotypes (John L. Hartman, IV).

5.3 Experimental concepts for genetic buffering analysis.

5.4 Experimental platforms for global genetic interaction analysis.

6. Gene - Gene Epistasis and Gene - Environment Interactions Influence Diabetes and Obesity (Sally Chiu, Adam L. Diament, Janis S. Fisler, and Craig H. Warden).

6.1 Gene - gene and gene - environment interactions.

6.2 Epistasis and gene - environment interactions in obesity and diabetes.

6.3 Animal models for detecting gene interactions.

6.4 Gene - gene interaction in obesity and diabetes.

6.5 Dietary fat in obesity and diabetes.

6.7 Future directions and conclusions.

7. Nutrients and Gene Expression (Gertrud U. Schuster).

7.2 SREBPs and ChREBP: transcription factors, influenced by dietary lipids and glucose.

7.3 Superfamily of nuclear receptors.

7.4 Nuclear receptors- -structure and function.

7.5 Nuclear receptors as metabolic sensor.

7.7 Phytoesterogens - nutrients mimicking estrogens .

8. Green Tea Polyphenols and Cancer Prevention (Shangqin Guo and Gail Sonenshein).

8.2 Green tea and cancer epidemiology.

8.4 Mechanisms of green tea action: molecular signaling pathways and gene targets.

8.5 Clinical studies and the promise of tea in combinatorial therapy.

8.6 Future directions and concluding remarks.

9. Molecular Mechanisms of Longevity Regulation and Calorie Restriction (Su - Ju Lin).

9.1 A conserved longevity factor, Sir2.

9.2 Molecular mechanisms of calorie reduction.

9.3 Role of NAD/NADH ratio in aging and human diseases.

9.4 Possible CR mimetics - small molecules that regulate Sir2 activity.

9.5 The molecular targets of Sir2 proteins in mammals.

9.6 A possibly conserved longevity pathway.

9.7 Applications to nutritional genomics.

10. Maternal Nutrition: Nutrients and Control of Expression (Craig A. Cooney).

10.2 DNA methylation, epigenetics, and imprinting.

10.3 Endogenous retroviruses and genome integrity.

10.4 Epigenetics and nutrition can greatly modulate genetic predispositions.

10.5 Yellow mouse models of epigenetic regulation.

10.6 A variety of maternal effects are seen in mice.

10.7 Rat models of maternal effects leading to diabetes.

10.8 Maternal effects on memory and aging.

10.9 Epigenetic effects in foxes.

10.10 Epigenetic effects related to reproduction in humans.

10.11 Nutrients and compounds that may affect early development and epigenetics.

11. Nutrient - Gene Interactions Involving Soy Peptide and Chemopreventive Genes in Prostate Epithelial Cells (Mark Jesus M. Magbanua, Kevin Dawson, Liping Huang, Wasyl Malyj, Jeff Gregg, Alfredo Galvez, and Raymond L. Rodriguez).

11.2 Lunasin structure and function.

11.3 Lunasin treatment of prostate cancer and gene expression profiling.

11.4 Lunasin - induced gene expression profiles.

11.6 Genes involved in suppression of cell proliferation.

11.7 Mitotic checkpoint genes.

11.8 Genes involved in protein degradation.

11.9 Connexin 43 gene for the gap junction protein.

11.10 Target verification using RT - PCR.

12. Enzymes Lose Binding Affinity (increase Km) for Coenzymes and Substrates with Age: A Strategy for Remediation (Bruce N. Ames, Jung H. Suh, and Jiankang Liu).

12.2 Remediation by high B vitamin intake of variant enzymes with poor binding affinity (Km) for coenzymes.

12.3 Deformation of proteins in mitochondria with aging.

12.4 Non - mitochondrial enzymes that are deformed with age.

13. Dietary and Genetic Effects on Atherogenic Dyslipidemia (Ronald M. Krauss, MD, and Patty W. Siri, PhD, MS).

13.1 LDL represent a heterogeneous population.

13.2 LDL subclasses are influenced by genes and the environment.

14. Genistein And Polythenols in the Study of Cancer Prevention: Chemistry, Biology, Statistics and Experimental Design (Stephen Barnes, David B. Allison, Grier P. Page, Mark Carpenter, Gary L. Gadbury, Sreelatha Meleth, Pamela Horn-Ross, Helen Kim, Coral A. Lamartinere, and Clinton J. Grubbs).

14.3 Chemistry of the polyphenols.

14.4 Uptake, distribution, metabolism, and excretion of the polyphenols.

14.5 Polyphenols and cancer prevention.

14.6 Mechanisms of action of polyphenols.

14.7 Importance of timing exposure to polyphenols.

14.8 Assessing events leading to cancer-low dimensional approaches.

14.9 Statistical consequences of high dimensional approaches.

14.10 High dimensional systems and the importance of the false discovery rate.

14.11 DNA microarray analysis-high dimensional research into gene expression.

14.12 Proteomics analysis-an even bigger challenge.

14.13 Statistical problems with fold-change in DNA microarray and proteomics analyses.

14.14 Design in experiments involving DNA microarray and proteomics analysis.

14.16 Role of the computer in high dimensional analysis.

15. Susceptibility to Exposure to Heterocyclic Amines from Cooked Food: Role of UDP-glucuronosyltransferases (Michael A. Malfatti and James S. Felton).

15.2 Genetic susceptibility.

15.4 UDP-glucuronosyltransferase biochemistry.

15.5 UDP-glucuronosyltransferase gene structure.

15.6 Substrate specificity and selectivity.

15.7 Tissue distribution of UPD-glucuronosyltransferase.

15.10 UDP-glucuronosyltransferase and cancer susceptibility.

15.11 Heterocyclic amine carcinogens in food.

15.12 Carcinogenicity of PhIP.

15.14 UDP - glucuronosyltransferase and PhIP risk susceptibility.

16. The Informatics and Bioinformatics Infrastructure of a Nutrigenomics Biobank (Warren A. Kibbe).

16.2 Next generation biobanks.

16.3 Intended audience for this chapter.

16.4 Regulatory and policy environment.

16.5 HIPAA Health Insurance Portability and Accountability Act of 1996.

16.8 Biobanking in clinical trials.

16.9 Data standards/semantic interoperability.

16.10 Other Standards Bodies: CDISC.

16.11 Informatics infrastructure.

16.13 Separation of the clinical trial/patient identity management from the genotype/phenotype repository.

16.14 Database architecture/ data modeling.

16.16 Pulling it all together.

17. Biocomputation and the Analysis of Complex Datasets in Nutritional Genomics (Kevin Dawson, Raymond L. Rodriguez, Wayne Chris Hawkes, and Wasyl Malyj).

17.2 Nutritional genomics is part of high - throughput biology.

17.3 Gene expression arrays.

17.4 Proteomics and metabolomics data.

17.5 Sources of complexity in nutritional genomics.

17.6 Data sets in nutritional genomics.

17.7 The level of complexity in gene expression experiments.

17.8 Dimensionality reduction methods.

17.9 Case study (microarray experiment of a dietary - intervention).

18. Cultural Humility: A Contribution to Health Professional Education in Nutrigenomics (Melanie Tervalon).

18.4 Goals and objectives: curriculum content.

18.5 Goals and objectives: curriculum design.

18.6 Curriculum structure and content: didactics, small groups and videotaping.

19. Nutrients and Norms: Ethical Issues in Nutritional Genomics (David Castle, Cheryl Cline, Abdallah S. Daar, Charoula Tsamis, and Peter A. Singer).

19.1 Proactive ethics and nutritional genomics.

19.2 Claims of health benefits arising from nutrigenomics.

19.3 Managing nutrigenomic information.

19.4 Methods for delivering nutrigenomic services.

19.5 Nutrigenomic products.

19.6 Access to nutrigenomics.


Veterans and Agent Orange: Update 2012 (2014)

Based on new evidence and a review of prior studies, the committee for Update 2012 did not find any new significant associations between the relevant exposures and adverse outcomes in future generations. Current evidence supports the findings of earlier studies that

&bull No adverse outcomes in future generations had sufficient evidence of an association with the chemicals of interest.

&bull There is limited or suggestive evidence of an association between the chemicals of interest and spina bifida.

&bull There is inadequate or insufficient evidence to determine whether there is an association between parental exposure to the chemicals of interest and birth defects other than spina bifida, childhood cancers, or disease in their children as they mature or in later generations.

The original report in this series, Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam (VAO IOM, 1994) contained a single chapter devoted to reproductive outcomes, as was the case through the publication of Veterans and Agent Orange: Update 2000, hereafter referred to as Update 2000 (IOM, 2001). (Analogous shortened names are used to refer to the updates for 1996, 1998, 2002, 2004, 2006, 2008, and 2010 [IOM, 1996, 1999, 2003, 2005, 2007, 2009, 2011]). In Update 2002, the chapter&rsquos concerns were extended to include consideration of developmental effects. In Update 2008, the chapter also addressed the possibility that adverse effects of exposure to the chemicals in the

herbicides used by the military in Vietnam might extend beyond the children of exposed people and affect future generations.

The committee for the current update decided to divide the material into two separate chapters. Chapter 9 contains information on reproductive outcomes affecting the parental generation and the course of gestation. The current chapter focuses and expands on issues related to possible adverse effects in future generations&mdashboth the children of Vietnam veterans and their offspring in turn. Since its inception, the VAO series has considered birth defects (primarily limited to problems detectable at birth or within the first year of life) and childhood cancers (usually restricted to particular cancers that characteristically appear in infants and children and are diagnosed before the age of 18 years). Because of concerns increasingly expressed by veterans and corresponding interest in the Department of Veterans Affairs, in Update 2010 the attention of VAO committees was extended to include all types of medical issues occurring in the veterans&rsquo children regardless of age and to include such problems in successive generations. It is hoped that by devoting a separate chapter to the possible &ldquopost-birth&rdquo problems of the progeny of Vietnam veterans, we can more clearly present the evidence for maternally and paternally mediated effects separately because the underlying biology is quite distinct in the two cases.

This chapter summarizes the scientific literature published since Update 2010 that investigated associations between parental exposure to herbicides and adverse effects on offspring, including future generations, throughout their life spans. The epidemiologic literature considered in this chapter includes studies of a broad spectrum of effects in children of Vietnam veterans or other populations occupationally or environmentally exposed to the herbicides sprayed in Vietnam or to the contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Because some polychlorinated biphenyls (PCBs), some polychlorinated dibenzofurans (PCDFs), and some polychlorinated dibenzodioxins (PCDDs) other than TCDD have dioxin-like biologic activity, studies of populations exposed to PCBs or PCDFs were reviewed if their results were presented in terms of TCDD toxic equivalents (TEQs). Although all studies reporting TEQs based on PCBs were reviewed, studies that reported TEQs based only on mono-ortho PCBs (which are PCBs 105, 114, 118, 123, 156, 157, 167, and 189) were given very limited consideration because mono-ortho PCBs typically contribute less than 10% to total TEQs, based on the World Health Organization (WHO) revised toxicity equivalency factors of 2005 (La Rocca et al., 2008 van den Berg et al., 2006). Although some multigenerational studies have been conducted on laboratory animals, to date there have not been human studies of descendants beyond the first generation for the chemicals of interest (COIs).

Because most Vietnam veterans are men, the primary focus of the VAO series has been on potential adverse effects of herbicide exposure on men. For non-reproductive outcomes, the etiologic importance of the exposed person&rsquos sex does not play a dominant role but for the possible transmission of adverse effects to

future generations, it is critically important, from the perspective of the biologic mechanism, which parent experienced the exposure in question. About 8,000 women served in Vietnam (H. Kang, US Department of Veterans Affairs, personal communication, December 14, 2000), so adverse outcomes in the offspring of female Vietnam veterans are a concern. Exposure scenarios in human populations and experimental animals studied differ in their applicability to our population of concern according to whether the exposed parent was male or female, and it is necessary to evaluate the effects of maternal and paternal exposure separately. As will be noted repeatedly, however, almost all Vietnam veterans were men, but the amount of research providing reliable information on the consequences of paternal exposure is extremely sparse not only for the COIs in the VAO report series but also for the full array of environmental agents that may pose threats to the health of future generations.

In addition, for published epidemiologic or experimental results to be fully relevant to evaluation of the plausibility of reproductive effects in Vietnam veterans, whether female or male, the veterans&rsquo exposure needs to have occurred before conception. With the possible exception of female veterans who became pregnant while serving in Vietnam, pregnancies that might have been affected occurred after deployment, when primary exposure had ceased. In the case of pregnancies of women who have previously been substantially exposed to the lipophilic dioxins, direct exposure of the fetus throughout gestation is possible owing to mobilization of toxicants from the mother&rsquos adipose tissue. The chapter also addresses the biologic plausibility of adverse effects on offspring mediated by male veterans through semen transmission during pregnancies that occurred after deployment.

The categories of association and the approach to categorizing the health outcomes are discussed in Chapters 1 and 2. To reduce repetition throughout the report, Chapter 6 characterizes the study population and presents design information on new publications that report findings on multiple health outcomes or that revisit study populations considered in earlier updates.

There have been few offspring studies of the four herbicides in question, particularly picloram and cacodylic acid, and those studies generally have shown toxicity only at very high doses, so the preponderance of the following discussion concerns TCDD, which outside controlled experimental circumstances usually occurred in a mixture of dioxins (dioxin congeners in addition to TCDD).

Because TCDD is stored in fat tissue and has a long biologic half-life, internal exposure at generally constant concentrations may continue after episodic, high-level exposure to external sources has ceased. If a person had high exposure, there may still be large amounts of dioxins stored in fat tissue, which may be mobilized, particularly at times of weight loss. That would not be expected to be the case for nonlipophilic chemicals, such as cacodylic acid.

The mechanisms of possible effects on offspring differ greatly for men and women exposed to the COIs during their service in Vietnam. A father&rsquos (paternal) contribution to adverse effects in his offspring is limited mainly to the contents of the fertilizing sperm, which had long been believed to consist almost exclusively of greatly condensed, transcriptionally inert deoxyribonucleic acid (DNA) for half the paternal genome (a haploid set of chromosomes). As a result, it was thought that any paternally-derived damage to the embryo or offspring would have to arise from changes in sequence or arrangement of the sperm&rsquos DNA the fact that dioxins have not been shown to be genotoxic fostered skepticism that adverse outcomes in offspring could arise from paternal exposure to the COIs. More recently, however, it has been recognized that sperm also carry a considerable collection of ribonucleic acid (RNA) fragments (Kramer and Krawetz, 1997 Krawetz et al., 2011). Although ribosomal (rRNAs) and messenger RNAs (mRNAs) have been detected in mature sperm, as yet, any roles they may play in fertilization or development have not been delineated. Functionality has been demonstrated for several of the small RNAs found in mature sperm (Krawetz, 2005) they have been found to play critical roles in early embryonic development (Hamatani, 2012 Suh and Blelloch, 2011) and epigenetic determinations (Kawano et al., 2012). Epigenetic effects are ones that result in permanent (heritable) changes in gene expression without a change in DNA sequence arising from modification to DNA (usually involving methylation) or to other cellular components such as histones and RNAs (Jirtle and Skinner, 2007). Alterations in DNA expression arising from epigenetic modification of an individual&rsquos somatic cell lines may not be manifested for long periods of time. In epigenetic transgenerational inheritance, an alteration in the germ line must be maintained for at least three generations following in utero exposures and for at least two generations after adult exposures (Jirtle and Skinner, 2007), so this process requires exposure precisely at the time in germ-line development when epigenetic programming is being established (Skinner et al., 2010). Therefore, paternally-derived adverse outcomes in offspring associated with exposure to the COIs could be mediated not just by genetic alterations of DNA, but also by epigenetic modifications to components of sperm in addition to their DNA (Krawetz, 2005). There is also a more remote possibility, if body burden were sufficiently high, that TCDD exposure might occur through absorption of seminal plasma through the vaginal wall, which could affect gestating offspring in an otherwise unexposed mother.

A mother&rsquos (maternal) contribution to a pregnancy and offspring is obviously more extensive, and any damage to the resulting offspring or later generations can result from epigenetic changes in the egg or from direct effects of exposure on the fetus during gestation and on the neonate during lactation. Herein, we review biologic plausibility and relevant data on female veterans and male veterans separately because the underlying pathways for adverse effects in offspring are so different.

Paternal Preconception and Postconception Exposure

There is particular interest in the possibility of paternally-mediated effects on offspring and later generations because the vast majority of Vietnam veterans are male. There are two feasible pathways through which TCDD and other COIs from paternal exposures could lead to developmental and later life effects in offspring and potentially future generations. One involves direct alterations in the paternal fertilizing sperm cells that transmit adverse effects to resulting offspring through genetic or epigenetic mechanisms as delineated in Chapter 4. Those effects would occur before conception. The other involves transmission of the contaminants to a female partner through seminal fluid during an established pregnancy, that is, after conception.

There is no evidence that dioxins can mutate DNA sequences thus, genetic changes in sperm genes&mdashas has been shown in connection with irradiation or the anticancer drug cyclophosphamide (Codrington et al., 2004)&mdashdue to preconception exposures to TCDD are not likely. There is potential for TCDD to alter sperm cells of adults before fertilization through epigenetic pathways. The sperm epigenome is distinct from that of the egg (oocyte) or somatic cells (all other nongamete cells in the body). The mature sperm cell has less global methylation than somatic cells and unique DNA methylation marks (particularly on paternally imprinted genes) that put the gametes in a pluripotent state before fertilization (Hales et al., 2011). Chemical alterations of methylation foci in DNA of adult sperm have the potential to contribute to permanent effects in offspring, as demonstrated in fetal alcohol syndrome (Jenkins and Carrell, 2012a Ouko et al., 2009). During spermatogenesis in the adult, most sperm histones are replaced by protamines, which render the sperm transcriptionally quiescent and permit extensive DNA compaction. But recent evidence has shown that some core histones are retained in human sperm at sites that are important during embryo development, so their perturbation by exogenous chemicals remains a possibility (Hammoud, et al., 2009). That is particularly important because although genome-wide DNA demethylation occurs in paternal DNA after-fertilization and would erase most sites that have been reprogrammed by chemicals, histone modification patterns are retained and thus may transmit chemical-induced alterations across generations (Puri et al., 2010). Finally, despite the exclusion of almost all cytoplasm, mature sperm have been found to carry a diverse spectrum of RNAs, including mRNAs, rRNAs, and noncoding RNAs, which may affect the developing embryo (Hamatani, 2012 Krawetz, 2005 Krawetz et al., 2011 Suh and Blelloch, 2011). It has recently been demonstrated that small RNAs of paternal origin may direct epigenetic modifications during embryo development and lead to changes in phenotype later in life (Hales et al., 2011). Heavy metals have been

shown to interact with sperm&rsquos nuclear proteins, and this mechanism is suspected to be a basis of paternally-mediated lead toxicity (Quintanilla-Vega et al., 2000). Disturbances in the establishment of the epigenetic marks in mature sperm may change cell fate in the early embryo and have effects throughout development and postnatal life (Jenkins and Carrell, 2012b). Direct evidence of dioxinmediated changes in the epigenome of mature sperm is not available, but dioxins have been shown to modify DNA methylation in microRNAs in somatic cells (Hou et al., 2011), so the pathway is biologically plausible.

Contaminants such as TCDD that are present in the tissues and blood of exposed males can be transported as parent compounds or metabolites into seminal fluid, the noncellular component of the ejaculate. Typically, concentrations of contaminants in seminal fluid are lower than those in serum, but direct assessments of ratios of serum to seminal fluid in TCDD have not been reported. Seminal-fluid contaminants can be transmitted to a female during sexual intercourse and be absorbed through the vaginal wall if concentrations are high, they will potentially affect a current pregnancy (Chapin et al, 2004 Klemmt and Scialli, 2005). TCDD and other persistent organic pollutants have been identified and quantified in seminal plasma of exposed men, including Vietnam veterans (Schecter et al., 1996 Schlebusch et al., 1989 Stachel et al., 1989) thus, this transmission route is theoretically possible. In the Schecter (1996) study, serum TCDD was measured in 50 Vietnam veterans from Michigan who had confirmed or self-reported potential for Agent Orange exposure and had blood drawn an average of 26 years after the possible exposure. Of those, 6 had TCDD greater than 20 parts per trillion (ppt) on a lipid-adjusted basis, and this supports the idea that some veterans did have high initial exposures. A subgroup of 17 men contributed semen at the time of blood draw, and dioxin congeners were analyzed in three randomly pooled samples&mdasha process necessary to provide sufficient volume for chemical analysis. Although measured concentrations were very low, the results documented the existence of dioxins and dibenzofurans in seminal plasma of the veterans long after possible Agent Orange exposure. Because results on serum and semen concentrations could not be linked for individual veterans and because it is unknown whether any of the subjects who had high serum dioxin concentrations after 26 years contributed semen for the seminal-fluid measurements, the value of this information is slight. Seminal-fluid concentrations of TCDD and related chemicals closer to the period of exposure in Vietnam have not been determined, so it is not possible to assess the clinical consequences of this exposure route for female partners and gestating offspring. Banked Operation Ranch Hand specimens, however, might provide a valuable resource for comparing TCDD concentrations in serum and seminal fluid.

Furthermore, despite the potential for a seminal-fluid route of exposure, the

critical question of dose sufficiency remains unanswered, that is, Could absorbed TCDD concentrations be high enough to transmit adverse effects in the fetus? To that end, one must take into account several factors: the volume of seminal plasma is relatively low (1&ndash5 mL) because of leakage, only a fraction of seminal constituents are absorbed across the vaginal wall and dilution of absorbed chemicals in the female bloodstream (that is, in a high volume) before transmission across the placenta is estimated at 3 orders of magnitude or more (Klemmt and Scially, 2005), and this reduces a serum concentration of 20 ppt to a scale of parts per quadrillion (10 &ndash15 ). Although studies to address the issue directly have not been undertaken, the dilution factor makes adverse fetal and offspring outcomes as a consequence of seminal plasma exposures to TCDD during pregnancy extremely unlikely.

Empirical Epidemiologic Evidence on Paternal Transmission

The idea that exposure of either parent to a toxicant before conception could result in an adverse outcome in offspring is not new and remains a topic of much interest. Epidemiologic studies have reported occasional findings of paternally transmitted adverse outcomes associated with paternal exposures to certain agents, but none has been replicated convincingly. Even in instances in which an agent is recognized as mutagenic or potentially carcinogenic for exposed men, adverse consequences have not been demonstrated in offspring. For example, the hypothesis was extensively investigated in the early 1990s in relation to fathers&rsquo exposure to ionizing radiation before conception and an increase in leukemia in their offspring. The initial study (Gardner et al., 1990) was conducted in men who worked at the Sellafield nuclear facility in West Cumbria, United Kingdom. It was presumed that the men were exposed to radiation as a result of working at Sellafield. An association was found between fathers&rsquo radiation exposures before conception and an increase in leukemia among their children. However, later studies have failed to confirm that finding (Draper et al., 1997 Kinlen, 1993 Kinlen et al., 1993 Parker et al., 1993). Similarly, rigorous followup of children of atomic-bomb survivors has not demonstrated increased risks of cancer or birth defects (Izumi et al., 2003 Schull, 2003), and other studies of effects (birth defects and cancer) in the children of male cancer survivors after chemotherapy or radiation treatment have found little support for paternal transmission (Chow et al., 2009 Dohle, 2010 Howell and Shalet, 2005 Madanat-Harjuoja et al., 2010), although sperm and fertility clearly are adversely effected (Green et al., 2010).

The committee was unable to find a single instance of epidemiologic evidence that convincingly demonstrated that paternal exposure to any particular chemical before conception resulted in cancer or birth defects in offspring. However, there are few data for addressing the hypothesis of paternal exposure and adverse effects in human offspring in which the exposure occurred before conception only to the father and was measured with an objective dosimeter. Thus, it is

difficult to assert conclusively that the available epidemiologic evidence supports or does not support paternal transmission considerable uncertainty remains on many fronts and would presumably vary by agent and mode of exposure. Several systematic reviews of the topic have been conducted (Chia and Shi, 2002 Weselak et al., 2007, 2008 Wigle et al., 2007, 2008) and have not established firm relationships between specific agents and particular effects in offspring. Paternal occupation (by job title or job-exposure matrices) has been linked to increased risk of selected birth defects (Desrosiers et al., 2012 Fear et al., 2007 Shaw et al., 2002), and neuroblastoma (De Roos et al., 2001a,b). Moreover, increased risks of childhood brain cancer have been reported in relation to paternal exposure to selected pesticides, particularly herbicides and fungicides (van Wijngaarden et al., 2003), although the authors noted considerable uncertainty in the robustness of the findings. Therefore, the hypothesis that paternal preconception exposure to toxic agents may result in harm to their children remains unresolved in part because of the sparseness of epidemiologic research on the subject.

A mother&rsquos exposures can affect a pregnancy and the resulting offspring far more extensively than paternal exposures. Because of the long half-life of TCDD and its bioaccumulation in adipose tissues, women exposed to Agent Orange in Vietnam would have potential to expose their offspring to TCDD directly during later pregnancies. Thus, damage to the resulting offspring or future generations could result from epigenetic changes in an egg before conception or from direct effects of exposure on the fetus during gestation and on the neonate during lactation. Dioxin in the mother&rsquos bloodstream can cross the placenta and expose the developing embryo and fetus. Furthermore, mobilization of dioxin during pregnancy or lactation may be increased because the body is drawing on fat stores to supply nutrients to the developing fetus or nursing infant. TCDD has been measured in circulating human maternal blood, cord blood, placenta, and breast milk (Suzuki et al., 2005), and it is estimated that an infant breastfed for 1 year accumulates a dose of TCDD that is 6 times as high as an infant not breastfed (Lorber and Phillips, 2002). Offspring effects of maternal exposures may not be manifested immediately and could be a result of dioxin-mediated reprogramming of developing organs and lead to disease onset later in life.

An emerging field of research referred to as the developmental basis of adult disease (Barker et al., 2012) has been investigating maternal nutritional exposures, stress, and alcohol exposure, and more recent studies have involved exposures to TCDD and other environmental toxicants. The molecular basis of the later-life effects is believed to be primarily epigenetic. Maladies that may be manifested later in life include neurologic and reproductive disorders, thyroid changes, and adult-onset cancers. Furthermore, germ cells (eggs and spermatogonia) in offspring undergo critical developmental stages during fetal life, and

emerging evidence demonstrates that fetal exposures are capable of altering the germ cells epigenetically and of resulting in transmission of adverse effects to future generations (transgenerational inheritance).

Laboratory animal studies have established that TCDD can affect development, so a connection between TCDD exposure and effects on offspring, including developmental disruption and disease onset in later life, is biologically plausible. It has been established in several animal studies that TCDD at high doses is a potent teratogen. However, definitive conclusions based on animal studies about the potential for TCDD to cause later-life toxicity in human offspring are complicated by differences in sensitivity and susceptibility among individual animals, strains, and species by differences in route, dose, duration, and timing of exposure in experimental protocols and real-world exposure and by differences in the toxicokinetics of TCDD between laboratory animals and humans. Experiments with 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) indicate that they have subcellular effects that could constitute a biologically plausible mechanism for developmental effects, but only at very high doses. There is insufficient information on picloram and cacodylic acid to assess the biologic plausibility of their developmental or delayed effects in offspring.

Chapter 4 presents more detailed toxicologic findings that are relevant to the biologic plausibility of the outcomes discussed here.

March of Dimes defines a birth defect as an abnormality of structure, function, or metabolism, whether genetically determined or resulting from an environmental influence during embryonic or fetal life (Bloom, 1981). Other terms, often used interchangeably, are congenital anomaly and congenital malformation. Major birth defects, which occur in 2&ndash3% of live births, are abnormalities that are present at birth and are severe enough to interfere with viability or physical well-being. Birth defects are detected in another 5% of babies through the first year of life. The causes of most birth defects are unknown. Genetic factors, exposure to some medications, exposure to environmental contaminants, occupational exposures, and lifestyle factors have been implicated in the etiology of birth defects (Kalter and Warkany, 1983). Most etiologic research has focused on the effects of maternal and fetal exposures, but as discussed in the beginning of this chapter, it is theoretically possible that epigenetic alterations of the paternal gamete caused by preconception exposures could result in paternally-mediated effects. It should be noted that a substantial amount of epidemiologic research on suspect toxic agents has been conducted, but has not definitively established paternal preconception exposures as a contributing factor to the occurrence of birth defects (Chow et al., 2009 Desrosiers et al., 2012 Dohle, 2010 Schull, 2003).

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to 2,4-D, 2,4,5-T or its contaminant TCDD, picloram, or cacodylic acid and birth defects in offspring. Additional information available to the committee responsible for Update 1996 led it to conclude that there was limited or suggestive evidence of an association between at least one of the COIs and spina bifida in the children of veterans there was no change in the conclusions regarding other birth defects. The committee for Update 2002, which reviewed the study of female Vietnam veterans (Kang et al., 2000) that reported significant increases in birth defects in their offspring, did not find those results adequate to modify prior conclusions, although Congress did mandate service-related status to a number of birth defects in the children of female Vietnam veterans. Later VAO committees have not encountered enough additional data to merit changing the conclusion that the evidence is inadequate to support an association between exposure to the COIs and birth defects (aside from spina bifida) in the offspring of either male or female veterans.

Summaries of the results of studies of birth defects and specifically of neural-tube defects that were reviewed in the current report and in earlier VAO reports are in Tables 10-1 and 10-2, respectively.

Update of the Epidemiologic Literature

No Vietnam-veteran, occupational, or case-control studies of exposure to the COIs and birth defects have been published since Update 2010.

Since Update 2010, three studies have examined maternal exposure to the COIs in relation to congenital cryptorchidism or hypospadias two based on a Danish-Finnish joint prospective cohort (Krysiak-Baltyn et al., 2012 Virtanen et al., 2012) and one that used the US National Birth Defects Prevention Study (NBDPS), a population-based case-control study of congenital malformations that uses a multistate surveillance systems (Rocheleau et al., 2011).

Virtanen et al. (2012) examined placental concentrations of dioxins and PCBs in relation to congenital cryptorchidism in a nested case-control study within the joint prospective Danish-Finnish cohort study of the incidence of and risk factors for congenital cryptorchidism and hypospadias. Boys born in 1997&ndash2001 in Copenhagen were examined for cryptorchidism at birth and at the age of 3 months. In preterm boys who had undescended testis, cryptorchidism was diagnosed only if the testis remained undescended at the expected date of delivery. Midwives collected and froze placentas immediately after birth. The

US Air Force Health Study&mdashRanch Hand veterans vs SEA veterans (unless otherwise noted)

Verified birth defects in children born to AFHS veterans

High-exposure Ranch Hands relative to comparisons

CDC Birth Defects Study&mdashHospital records reviewed for offspring of 7,924

Vietnam veterans and 7,364 non&ndashVietnam veterans

General Birth Defects Study&mdashhospital records

Birth defects&mdashblack Vietnam veterans

Vietnam veterans identified through CDC Metropolitan Atlanta Congenital Defects Program

Multiple birth defects with reported exposure

EOI-5: cleft lip with or without cleft palate

Reproductive outcomes&mdashinterview data

Children of veterans reporting high exposure

US VA Cohort of Female Vietnam Veterans

Female Vietnam-era veterans&mdashdeployed vs nondeployed (maternal exposure)

&ldquoModerate-to-severe&rdquo birth defects

State Studies of US Vietnam Veterans

Massachusetts Vietnam-era veterans

Vietnam veterans whose children were born at Boston Hospital for Women

All congenital anomalies (crude OR)

vs men without known military service

One or more major malformations (crude OR)

vs men without known military service

International Vietnam-Veteran Studies

Australian Vietnam Veterans&mdash58,077 men and 153 women who served on land or in Vietnamese waters during 5/23/1962&ndash7/1/1973 vs Australian population

Absent external body part

Vietnam veterans vs all other men

National service veterans&mdashVietnam service vs no Vietnam service

NIOSH Mortality Cohort (12 US plants, 5,172 male production and maintenance workers 1942&ndash1984) (included in IARC cohort as of 1997)

Wives of workers with measured serum TCDD in NIOSH cohort

Dow Workers with Potential TCDD Exposure and reproductive outcomes in offspring of 930 men working with chlorophenol 1939&ndash1975

Monsanto workers in Nitro, West Virginia, occupationally exposed and potentially exposed after 1949 explosion (1948&ndash1969)

Followup of current and retired 2,4,5-T production workers (n = 235 117 with chloracne exposure), 1948&ndash1969

Followup of 2,4,5-T production workers (204 exposed, 163 unexposed), 1948&ndash1969

Canada&mdashPregnancies with one or more birth defects in OFFHS

Use on farm, during 3 months before conception, of

Use on farm, during 3 months after conception, of

Canadian sawmill workers with exposure in upper 3 quartiles for any job held up to 3 months before conception

New Zealand&mdashFollowup of 2,4,5-T sprayers vs nonsprayers (n = 989)

Norway&mdashfarmers (maternal, paternal exposure)

United States&mdashMinnesota private pesticide appliers

All births with anomalies

Maternal, paternal, in utero exposure

Zones A and B&mdashtotal defects

Zones A and B&mdashmild defects

Persons in Missouri with documented TCDD soil contamination near residence (maternal, paternal, in utero exposure)

France&mdashCase-control study (2001&ndash2003 births) of urinary tract defects (n = 304) vs regional controls (n = 226) (same population as Cordier et al., 2004)

France&mdashBirths (1988&ndash1997): maternal residence in municipality with solid-waste incinerator vs not

Unknown or multifactoral etiology

Specific major anomalies with significant increases reported (of 23 categories reported)

Turkey&mdashCross-sectional study of MIH in Turkey n = 109 from industrialized community with high levels of PCDDs and n = 44 from low-industrialized community

United States&mdashRural or farm residents of Minnesota, Montana, North Dakota, South Dakota (maternal, paternal exposure)

Circulatory, respiratory anomalies

Musculoskeletal, integumental anomalies

United States&mdashPersons exposed to an electric-transformer fire in Binghamton, New York&mdashtotal birth defects (maternal, paternal exposure)

US National Birth Defects Prevention Study&mdashHypospadias and maternal herbicide exposure JEM to determine exposure from conception through first trimester of pregnancy (647 cases vs 1,496 controls)

Second- or third-degree hypospadias

Arkansas&mdashhypospadias as function of mother&rsquos residence within 500 m of agricultural pesticide use during gestation weeks 6&ndash16

Baltimore mothers in the BWIS exposed to herbicides during first trimester (maternal exposure)

Denmark/Finland&mdashRelationship between congenital cryptorchidism and PCBs and dioxins in breast milk (130 samples)

Denmark/Finland&mdashRelationship between congenital cryptorchidism and PCBs and dioxins in placentas 112 Finnish subjects (56 cases, 56 controls) and 168 Danish subjects (39 cases, 129 controls)

Finland&mdashFollowup of participants from previous case-control study of cleft lip and palate, n = 167 placenta tissue analyzed for PCDD/Fs and children assessed for MIH

Japan&mdashInvestigated multiple pregnancy outcomes in Japanese-infant deaths from congenital defects

New Zealand&mdashResidents of areas subject to aerial 2,4,5-T spraying

All birth malformations excluding dislocated or dislocatable hip

Spain&mdashResidents of agricultural areas&mdashat least median score on chlorophenoxy-herbicide exposure duration (months) index

The Netherlands&mdashInfants born in Zeeburg, Amsterdam, clinics 1963&ndash1965 with orofacial cleft (maternal exposure)

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid AFHS, Air Force Health Study BWIS, Baltimore-Washington Infant Study CDC, Centers for Disease Control and Prevention CI, confidence interval COI, chemical of interest EOI, exposure opportunity index IARC, International Agency for Research on Cancer JEM, job-exposure matrix MCPA, 4-chloro-2-methylphenoxyacetic acid MIH, molar incisor hypomineralization NIOSH, National Institute for Occupational Safety and Health nr, not reported ns, not significant OFFHS, Ontario Farm Family Health Study OR, odds ratio PCB, polychlorinated biphenyl PCDD, polychlorinated dibenzodioxins PCDF, polychlorinated dibenzofurans SEA, Southeast Asia TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin TEQ, (total) toxic equivalent VA, US Department of Veterans Affairs.

a Unless otherwise indicated, studies show paternal exposure.

b Given when available results other than estimated risk explained individually.

US Air Force Health Study&mdashRanch Hand veterans vs SEA veterans (unless otherwise noted)

Air Force Operation Ranch Hand personnel&mdashneural-tube defects

CDC Birth Defects Study&mdashHospital records reviewed for offspring of 7,924 Vietnam veterans and 7,364 non&ndashVietnam veterans

Vietnam veterans identified through CDC Metropolitan Atlanta Congenital Defects Program

Military records indicate opportunity for exposure

US CDC Vietnam Experience Study&mdashCross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

VES cohort&mdashreproductive outcomes

Vietnam veterans&rsquo children

Non&ndashVietnam veterans&rsquo children

Vietnam veterans&rsquo children

Non&ndashVietnam veterans&rsquo children

Australian Vietnam Veterans&mdash58,077 men and 153 women who served on land or in Vietnamese waters during 5/23/1962&ndash7/1/1973 vs Australian population

Australian Vietnam veterans&mdashneural-tube defects

Norwegian farmers&mdashspina bifida (maternal, paternal exposures)

Tractor spraying equipment

Tractor spraying equipment, orchards, greenhouses d

United States&mdashbirth defects in children born to licensed pesticide appliers in Minnesota linked to state birth registries

Persons in Missouri with documented TCDD soil contamination near residence (maternal, paternal, in utero exposure)

France&mdashPopulation-based birth defects registry in Rhône-Alpes region (1988&ndash1997): maternal residence in municipality with solid-waste incinerator vs not

Canada&mdashBritish Columbian sawmill workers with exposure in upper 3 quartiles for any job held up to 3 months before conception

New Zealand&mdashResidents of areas subject to aerial 2,4,5-T spraying

The Netherlands&mdashChildren of Dutch farmers who were born with spina bifida (1980&ndash1992), 470 cases vs 456 healthy controls

Spina bifida&mdashmoderate, heavy exposure

NOTE: 2,4,5-T, 2,4,5-trichlorophenoxyacetic acid CDC, Centers for Disease Control and Prevention CI, confidence interval COI, chemical of interest nr, not reported SEA, Southeast Asia TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin VES, Vietnam Experience Study.

a Unless otherwise indicated, studies show paternal exposure.

b Given when available results other than estimated risk explained individually.

c Of four neural-tube defects reported in Operation Ranch Hand offspring, two were spina bifida (high dioxin exposure), one spina bifida (low dioxin), one anencephaly (low dioxin) no neural-tube defects reported in comparison cohort 454 postservice births studied in Ranch Hand veterans 570 in comparison cohort.

d Greenhouse workers would not have been exposed to chemicals of interest.

e Calculated from data presented in the paper.

study included 56 Finnish cases and 56 controls that were individually matched on date of birth (± 2 weeks), parity, gestational age (± 1 week), smoking during pregnancy, and maternal diabetes. It also included 39 Danish subjects and 129 controls that were not matched on the above factors. Concentrations of 17 PCDD or PCDFs and 37 PCBs were measured and presented as total TEQs and as individual congeners. There were no significant differences between cases and controls in either the Finnish or Danish samples with respect to dioxin TEQs. Although there were some isolated and country-specific significant associations, none was replicated in all the countries, and concentrations of some congeners in controls exceeded those in cases. In a similarly designed study, Krysiak-Baltyn et al. (2012) examined breast-milk concentrations of PCBs and dioxins in relation to congenital cryptorchidism. Of the COIs measured, only dioxin-like OctoCDF concentrations in cases exceeded those in controls, and only in the Danish subset.

Using a job&ndashexposure matrix to estimate maternal herbicide exposure from conception through the first trimester of pregnancy, Rocheleau et al. (2011) examined the association of herbicide exposure with hypospadias in the NBDPS. Affected children and fetuses were identified through active case ascertainment by each surveillance program. Controls (1,496) were a random sample of all unaffected live births in the areas covered by the state-based surveillance systems, and cases (647) had a diagnosis of second- or third-degree hypospadias.

Maternal interviews were conducted no later than 24 months after delivery. The following covariates were examined for evidence of confounding: maternal age parity history of miscarriage, singleton, or multiple pregnancy gestational age and birth weight of the index infant maternal alcohol consumption or smoking during or before the first trimester use of a folic acid-containing supplement prepregnancy body mass index and several sociodemographic characteristics. The overall participation rate was about 70%. In general, participants exposed to herbicides were also exposed to insecticides or fungicides. In a model adjusted for all other pesticide classes, periconception herbicide exposure was not associated with second- or third-degree hypospadias (odds ratio [OR] = 0.99, 95% confidence interval [CI] 0.47&ndash2.10), but there were very few exposed cases (36).

Ren et al. (2011) conducted a case-control study of neural-tube defects (NTDs) in subjects recruited from four rural counties of the Shanxi Province in China in 2005&ndash2007. Cases were identified through a population-based birth-defects surveillance program. Healthy controls were individually matched to cases on sex, hospital of birth, mother&rsquos county of residence, and date of the mother&rsquos last menstrual period ("as close as possible"). Maternal interviews were conducted within 1 week of pregnancy termination or delivery to ascertain information on periconception use of folic-acid supplements smoking exposure exposure to pesticides, solvents, and heavy metals other environmental exposures and a variety of demographic, lifestyle, and reproductive history information. Placentas were collected at delivery or termination of NTD-affected pregnancies and measured for concentrations of polycyclic aromatic hydrocarbons, organochlorine pesticides, PCBs, and lipids. Models were adjusted for matching factors, in addition to maternal occupation, age, educational level, parity, folic-acid supplementation, passive smoking, and fever or influenza during pregnancy. Of the eight PCB congeners measured, six exhibited some dioxin-like activity (mono-ortho PCBs 105, 118, 156, 157, 167, and 189), but the measures of association were provided only as a sum, including also 206 and 209. Overall, there were no differences in the median placental concentrations of the total PCB sum between NTD cases (0.90 ng/g of lipid) and controls (0.87 ng/g of lipid).

2,4-D has been previously shown to be a teratogen, although at exposures that exceed maternal renal clearance, which are not relevant to Agent Orange exposure. A new study has shown for the first time that late in utero and early postnatal 2,4-D exposure can result in nephrotoxicity in offspring, although at one-sixth of the LD50 (Troudi et al., 2011). Other herbicides of interest can induce fetal malformations but typically only at high doses that are toxic to pregnant women. It is well established that TCDD is a potent teratogen in all laboratory species that have been studied, although the pattern of birth defects that are produced is often species-specific. Since Update 2010, studies have investigated the

mechanisms underlying various TCDD-induced birth defects in rodents and other animal models, including hydronephrosis, cleft palate, reproductive organ anomalies, neurogenesis, and perturbed heart, kidney, and lung development (Dong et al., 2010 Falahatpisheh et al., 2011 Jacobs et al., 2011 Lanham et al., 2012 Latchney et al., 2011 Neri et al., 2011 Tait et al., 2011 Yoshioka et al., 2012 Yuan et al., 2012). Those mechanisms have not been fully elucidated, but it has been demonstrated that TCDD-induced birth defects require the aryl hydrocarbon receptor (AHR) but do not require induction of cytochrome P4501A1 (Dragin et al., 2006 Jang et al., 2007 Mimura et al., 1997). When pregnant AHR-null mice are exposed to TCDD, the fetuses do not exhibit any of the typical developmental malformations associated with TCDD exposure, but fetuses of TCDD-exposed pregnant CYP1A1 null mice do. In addition, an AHR antagonist can attenuate TCDD-induced birth defects in mice. Thus, activation of the AHR by TCDD during development appears to be a key first step in mediating TCDD&rsquos developmental toxicity. Although structural differences in the AHR have been identified among species, it functions similarly in animals and humans. Therefore, a common mechanism mediated by the AHR in which tissue growth and differentiation processes are affected probably underlies the developmental toxicity of TCDD in humans and animals. It has been shown that antioxidant treatment provides protection against some TCDD-induced teratogenicity this suggests that reactive oxygen species might be involved in the pathways that lead to these structural changes (Jang et al., 2008). A few new studies indicate that stem cells and organ-specific progenitor cells may be direct targets and that maternal TCDD exposures interfer with proliferation and cell differentiation through the AHR and result in defects in organ morphogenesis (Latchney, 2011 Neri, 2011). Few laboratory studies of potential male-mediated developmental toxicity (and, specifically, birth defects) attributable to exposure to TCDD and herbicides have been conducted. Feeding of simulated Agent Orange mixtures to male mice produced no adverse effects in offspring (Lamb et al., 1981).

Embryonic and fetal development in rodents is sensitive to toxic effects of exposure to TCDD and dioxin-like chemicals. It is clear that the fetal rodent is more sensitive to adverse effects of TCDD than the adult rodent. Human data are generally lacking, however, and the sensitivity to developmental disruption in humans is less apparent, in part because contemporary studies of environmental dioxin exposure and birth defects have used extremely low exposures. The four studies since Update 2010 that have assessed exposure to relevant chemicals and congenital malformations all examined only maternal exposure, which is of little relevance to the majority of Agent Orange-exposed veterans. Furthermore, those environmental studies were conducted in populations exposed to contemporary concentrations, which may be too low for adverse fetal effects to be observed.

The studies were well designed and adjusted for important confounders, but they do not provide evidence of an association at these exposure levels.

There was one new study of the relationship between maternal exposure to dioxin-like, mono-ortho PCBs and NTDs in offspring, which found no association, and there were no new studies of parental exposure to 2,4-D, 2,4,5-T, TCDD, cacodylic acid, or picloram and spina bifida in offspring. The committee concludes that the evidence of an association between exposure to the COIs and spina bifida is still limited or suggestive. The evidence of an association between exposure to the COIs and other birth defects is inadequate or insufficient.

The American Cancer Society (ACS) estimated that 11,630 children less than 15 years old will receive a diagnosis of cancer in the United States in 2013 (ACS, 2013). Treatment and supportive care of children who have cancer have continued to improve. The 5-year survival rate for children who receive a cancer diagnosis has increased from less than 60% in the 1970s to more than 80% in 2013. Despite those advances, cancer remains the leading cause of death from disease in children less than 15 years old, and 1,310 deaths were projected for 2013 (ACS, 2013).

Leukemia is the most common cancer in children, accounting for about one-third of all childhood cancer cases. In 2010, ACS anticipated that almost 3,317 children would receive a leukemia diagnosis (ACS, 2010). Of those, almost 2,000 would have acute lymphocytic leukemia (ALL) most of the rest would have acute myeloid leukemia (AML). AML (International Classification of Diseases, Ninth Revision [ICD-9] 205) is also referred to as acute myelogenous leukemia or acute nonlymphocytic leukemia. For consistency, this report uses acute myeloid leukemia, or AML, regardless of usage in the source materials. ALL is most common in early childhood, peaking at the ages of 2&ndash3 years, and AML is most common during the first 2 years of life. ALL incidence is consistently higher in boys than in girls AML incidence is similar in boys and girls (NCI, 2001). Through early adulthood, ALL rates are about twice as high in whites as in blacks AML exhibits no consistent pattern in this respect. Chapter 8 contains additional information on leukemia as part of the discussion of adult cancer.

The second-most common group of cancers in children are those of the central nervous system&mdashthe brain and the spinal cord. Other cancers in children include lymphomas, bone cancers, soft-tissue sarcomas, renal cancers, eye cancers, and adrenal cancers. In contrast with adult cancers, relatively little is known about the etiology of most childhood cancers, especially about potential environmental risk factors and the effects of parental exposures.

Conclusions from VAO and Previous Updates

The committee responsible for VAO concluded that there was inadequate or insufficient evidence to determine whether there is an association between exposure to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid and childhood cancers. Additional information available to the committees responsible for Update 1996 and Update 1998 did not change that conclusion. The committee responsible for Update 2000 reviewed the material in earlier VAO reports and newly available published literature and concluded that there was limited or suggestive evidence of an association between exposure to at least one of the COIs and AML. After the release of Update 2000, investigators involved in one study discovered an error in their published data. The Update 2000 committee reconvened to evaluate the previously-reviewed and new literature regarding AML, and it produced Acute Myelogenous Leukemia (IOM, 2002). It reclassified AML from &ldquolimited/suggestive evidence of an association&rdquo to &ldquoinadequate evidence to determine whether an association exists.&rdquo

Table 10-3 summarizes the results of the relevant studies. The committees responsible for Update 2002, Update 2004, Update 2006, Update 2008, and Update 2010 reviewed the material in earlier VAO reports and in newly-available published literature and agreed that there remained inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and childhood cancers.

Update of Epidemiologic Literature

No Vietnam-veteran, occupational, or environmental studies of exposure to the COIs and childhood cancer have been published since Update 2010.

Two childhood-leukemia studies examined the relationship of herbicide exposures and leukemia risk. Chokkalingam et al. (2012) conducted a population-based epidemiologic study of 377 ALL cases and 448 controls in the Northern California Childhood Leukemia Study and examined association with self-reported exposure to indoor and outdoor household pesticides overall and in subgroups that had hypothesized susceptibility genotypes in 42 xenobiotic transport and metabolism genes. With no adjustment for confounders indicated, they found a borderline-significantly-increased risk of ALL with outdoor herbicide use before birth (OR = 1.46, 95% CI 1.04&ndash2.04) and with indoor insecticide use (OR = 1.29, 95% CI 0.97&ndash1.72).

Slater et al. (2011) examined infant leukemia risk in the Children&rsquos Oncology Group study associated with maternal exposure to herbicides at any time during the period from 1 month before conception throughout pregnancy, during only the

CDC Birth Defects Study&mdashHospital records reviewed for offspring of 7,924 Vietnam veterans and 7,364 non&ndashVietnam veterans

Vietnam veterans identified through CDC Metropolitan Atlanta Congenital Defects Program

US CDC Vietnam Experience Study&mdashCross-sectional study, with medical examinations, of Army veterans: 9,324 deployed vs 8,989 nondeployed

VES cohort&mdashreproductive outcomes

US veterans&mdashcase-control study of children&rsquos leukemia

Father ever served in Vietnam, Cambodia

< 1 year in Vietnam or Cambodia

> 1 year in Vietnam or Cambodia

Father ever served in Vietnam, Cambodia

< 1 year in Vietnam or Cambodia

> 1 year in Vietnam or Cambodia

International Vietnam-Veteran Studies

Australian Vietnam Veterans&rsquo children&mdashrevised validation study

Australian Vietnam veterans&rsquo children&mdash

This study, which incorrectly calculated expected number of AML cases, is updated by AIHW (2001) above

Tasmanian Veterans with Service in Vietnam

Cancer in children of Australian Vietnam veterans

OCCUPATIONAL&mdashHERBICIDE-USING WORKERS

Canada&mdashSawmill Workers in British Columbia 26,487 workers for &ge 1 year at 14 mills using chlorophenates 1950&ndash1985

Workers having a live birth within 1 yr after the initiation of employment

All workers&rsquo offspring&mdashincidence

Chlorophenate exposure: high- vs low-exposure subjects

All workers&rsquo offspring&mdashincidence

Chlorophenate exposure: high- vs low-exposure subjects

United States&mdashUS Agricultural Health Study&mdashprospective study of licensed pesticide sprayers in Iowa and North Carolina: commercial (n = 4,916), private/farmers (n = 52,395, 97.4% men), and spouses of private sprayers (n = 32,347, 0.007% men), enrolled 1993&ndash1997 followups with CATIs 1999&ndash2003 and 2005&ndash2010

Offspring of male pesticide applicators in Iowa from AHS

Maternal exposure to chlorophenoxy herbicides

Paternal exposure to chlorophenoxy herbicides

Seveso residents 0&ndash19 yrs old&mdash10-yr followup, morbidity, all exposure zones

Seveso residents 0&ndash19 yrs old&mdash10-yr followup, mortality, all exposure zones

Other International Environmental Studies

Canada&mdashALL in children (0&ndash9 yrs old) in households using herbicides (1980&ndash1993)

Exposure during pregnancy

Exposure during childhood

England&mdashRenal cancer in subjects (1&ndash15 yrs of age) with paternal occupation in agriculture

Norway&mdashCancer in children of agricultural workers (n = 1,275) identified in cancer registries (1965&ndash1991)

Children with AML whose parents purchased pesticides

US Case-Control Studies

Children&rsquos Oncology Group&mdashStudies association between infant leukemia and maternal herbicide exposure (443 cases vs 324 population controls)

Children&rsquos Oncology Group&mdashChildhood GCTs residential exposure to herbicides 6 months before conception, during gestation, through breastfeeding period

Children&rsquos Oncology Group&mdashParental occupational exposure to pesticide and GCTs, 1993&ndash2001 (253 cases vs 394 controls)

Children&rsquos Cancer Group&mdashexposure to pesticides, weed killers&mdashAML

Paternal exposure > 1,000 days

Maternal exposure > 1,000 days

California (Northern California Childhood Leukemia Study)&mdashExposure to &ldquooutdoor herbicides&rdquo and ALL (and variants in metabolic genes) (377 cases vs 448 controls)

Outdoor herbicide use before birth

California&mdashMaternal exposure to agricultural pesticide in class of &ldquoprobable human carcinogens&rdquo (including cacodylic acid) during 9 months before delivery

New York State&mdashNeuroblastoma risk in children, age &le 14 yrs of age (1976&ndash1987)

Maternal occupational exposure to insecticides

Paternal exposure to dioxin

International Case-Control Studies

Canada and United States&mdashStudy of Wilm&rsquos tumor

Maternal report of household use of herbicides from month before conception through child&rsquos diagnosis

Canada and United States&mdashNeuroblastoma risk in children (538 cases, 504 controls) from 139 hospitals in US and Canada (exposures as reported by both parents)

Pesticides in home (used ever)

Costa Rica&mdashparental occupational exposure to pesticide, childhood leukemia

Parental exposures in yr before conception to

Phenoxyacetic acids in yr before conception

West Germany&mdashpopulation-based study of childhood cancer (1993&ndash1997) (2,358 cases vs 2,588 controls)

Paternal exposure yr before pregnancy

Paternal exposure during pregnancy

Maternal exposure yr before pregnancy

Maternal exposure during pregnancy

Paternal exposure yr before pregnancy

Paternal exposure during pregnancy

Maternal exposure yr before pregnancy

Maternal exposure during pregnancy

France&mdashHematopoietic malignancies in children < 15 yrs of age (2003&ndash2004)

Maternal household herbicide use during pregnancy

Without paternal exposure

Without paternal exposure

Without paternal exposure

NOTE: 2,4-D, 2,4-dichlorophenoxyacetic acid AHS, Agricultural Health Study AIHW, Australian Institute for Health and Welfare ALL, acute lymphocytic leukemia AML, acute myeloid leukemia CATI, computer-assisted telephone interviewing CDC, Centers for Disease Control and Prevention CI, confidence interval COI, chemical of interest GCT, germ-cell tumor HL, Hodgkin lymphoma ICD, International Classification of Diseases NHL, non-Hodgkin lymphoma nr, not reported ns, not significant TCDD, 2,3,7,8-tetrachlorodibenzo-p-dioxin VES, Vietnam Experience Study.

a Unless otherwise indicated, studies show paternal exposure.

b Given when available results other than estimated risk explained individually.

c Of the 12, 9 were observed, 3 additional cases estimated to have occurred in portion of cohort whose data were not validated.

preconception period, and during only the pregnancy. They found no significant associations.

Paternal or maternal exposure to xenobiotics potentially could increase the susceptibility of offspring to cancer through multiple mechanisms. Susceptibility could be increased by inheriting a genetic predisposition, which by itself could increase the development of cancer or the likelihood of developing cancer after future exposure to a carcinogen the mother or father would transmit either an acquired genetic defect or an epigenetic alteration that predisposed the child to cancer. Alternatively, a maternally-mediated increase in susceptibility to childhood cancer could result from direct exposure of a child in utero or via lactation to a xenobiotic that induces epigenetic alterations that increase cancer susceptibility or is itself carcinogenic.

It has been shown that prenatal TCDD exposure of rats is associated with altered mammary-gland differentiation and an increase in the number of mammary adenocarcinomas (Brown et al., 1998). The demonstration that early postnatal TCDD exposure does not increase mammary-cancer risk (Desaulniers et al., 2004) does not contradict the finding that TCDD-induced changes in utero mediate the increase in cancer susceptibility (Fenton et al., 2000, 2002). Developmental epigenetic alterations may be involved in the prenatal effects. TCDD has been shown to suppress the expression of two tumor-suppressor genes, p16 Ink4a and p53, via an epigenetic mechanism that appears to involve DNA methylation (Ray and Swanson, 2004). Similarly, it was reported that prenatal TCDD exposure increases methylation of two growth-related imprinted genes, H19 and Igf2, in the developing fetus (Wu et al., 2004).

Although there is no direct evidence from animal models that TCDD increases the risk of childhood cancers, such as acute leukemia and germ-cell tumors, emerging research suggests that prenatal TCDD exposure can disrupt epigenetic imprinting patterns and alter organ differentiation and thus could contribute to an increased susceptibility to cancer later in life. Smith et al. (2005) showed that chromosomal rearrangements associated with childhood ALL are evident in the neonatal blood spots this suggests that childhood leukemias begin before birth, perhaps due to maternal exposures to genotoxic xenobiotics.

Two case-control studies considered childhood leukemias and herbicide use. One found a marginally significantly increased risk of ALL in association with maternal herbicide use before conception, and the other saw no increases in childhood leukemias related to maternal herbicide exposure shortly before or during

pregnancy. No new epidemiologic evidence specifically concerning the COIs and childhood cancers has been published since Update 2010.

On the basis of the evidence reviewed here and in previous VAO reports, the committee concludes that there is inadequate or insufficient evidence to determine whether there is an association between exposure to the COIs and childhood cancers.

In response to a special request from the Department of Veterans Affairs, continuing inquiries from veterans and their families, and increasing attention in research efforts, the committee for Update 2010 addressed whether it is feasible to assess associations between exposure to the herbicides sprayed in Vietnam and health effects that occur later in the lives of children of Vietnam veterans and even in their grandchildren such associations had not been formally reviewed in prior VAO updates. The previously-considered outcomes of birth defects observable within the first year of life and childhood cancer (diagnosis before the age of 18 years) were augmented to include all cancers and physical and neurobehavioral problems that might be manifested at any age. In addition, for the first time, the committee for Update 2010 explored the possibility of transgenerational effects resulting from exposure-related epigenetic changes in the parents or exposed fetuses that would lead to adverse health effects in later generations, such as grandchildren.

Conclusions from VAO and Previous Updates

The potential effect of maternal and paternal exposure of Vietnam veterans to herbicides on the development of disease other than cancer in their children after the first year of life or in later generations had not been considered in updates before Update 2010.

For Update 2010, epidemiologic studies that evaluated the potential for effects of maternal or paternal exposure to the COIs in offspring were identified. Rather than identifying specific diseases in offspring, much of the research involved the measurement of physiologic biomarkers that might indicate a potential for disease development later in life. The committee for Update 2010 therefore cautioned strongly that the clinical consequences of any observed changes are highly uncertain. The committee maintained its standard requirement for exposure specific to components of the herbicides sprayed in Vietnam. Although it may be physiologically possible for paternal exposure to cause changes in

offspring that are manifested later in life, none of the published epidemiologic studies assessed such potential. Thus, the observation of any changes reported in the studies discussed in this section of Update 2010 would be applicable only to children born to female Vietnam veterans during or after their deployment in Vietnam.

Changes Detected in Children After Parental Exposure

Thyroid Hormone Concentrations

Since Update 2010, there has been one additional epidemiologic study of childhood thyroid hormone concentrations associated with perinatal exposure to dioxins and dioxin-like PCBs. Leijs et al. (2012) conducted a followup study of 33 children 14&ndash19 years old in whose mothers&rsquo breast milk PCDD or PCDF exposure was determined. All children were born in the Amsterdam-Zaandam region. Spearman&rsquos correlations were calculated by comparing PCDD, PCDF, and dioxin-like PCB TEQs with childhood triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), thyroxine-binding globulin (TBG), and thyroid-stimulating hormone (TSH) concentrations. Laboratory methods for measuring thyroid hormone were not provided. There was no correlation between perinatal dioxin exposure and T3, T4, FT4, TBG, or TSH. There was a significant correlation between dioxin-like PCB TEQs and childhood T3, but the magnitude was not provided the significance level was p = 0.047. Those results conflict with the results of the Nagayama et al. (1998) study however, the Leijs et al. (2012) study was small, and no covariate adjustment was performed for potentially-important factors, such as the child&rsquos age and sex, the mother&rsquos age, and the mother&rsquos smoking or alcohol consumption during pregnancy.

Cognitive or Motor Development

Since Update 2010, there has been one additional study of infant neurobehavioral development in relation to prenatal dioxin exposure. Nishijo et al. (2012) examined the association between dioxin exposure and infant growth and development in 210 mother-infant pairs that resided in dioxin-contaminated districts near the Da Nang airbase in Vietnam. Full-term babies from uncomplicated deliveries were recruited in 2008&ndash2009. Breast milk was collected 1 month after birth and analyzed for 7 PCDDs and 10 PCDFs. Maternal interviews provided detailed covariate data, and pregnancy and delivery information was obtained from the obstetricians. All infants were breastfed until 4 months after birth. The duration of residence in the contaminated districts was directly related to PCDD and PCDF TEQ exposure quartile and maternal age. In boys, statistically-significant decrements in expressive communication skills as measured by the Bayley Scales of Infant and Toddler Development III (BSID-III) at the age of 4 months were noted

in the 4th quartile of exposure relative to the 1st. Although the differences were not statistically significant, infants of both sexes in the highest quartile of prenatal exposure exhibited lower cognitive scores on the BSID-III (about 6 points than the 1st quartile in boys and 4 points in girls) and lower total motor scores (about 4 points in boys and 3 points in girls). However, measures of neurodevelopment in very early life are generally unstable.

Immune-Cell Populations and Prevalence of Allergies or Asthma in Children

Since Update 2010, there has been one additional study of allergies and infections during infancy in relation to prenatal exposure to dioxin-like compounds. Miyashita et al. (2011) examined allergies and infections in 364 mother-infant pairs enrolled during 2002&ndash2005 in the Hokkaido Study on Environment and Children&rsquos Health (Sapporo, Japan). Third-trimester maternal blood concentrations of PCDDs, PCDFs, and dioxin-like PCBs were measured, and total maternal dioxin TEQs were calculated. Covariates (including exposure to environmental tobacco smoke, maternal education, annual household income, and maternal dietary intake of fish and meat during pregnancy) were assessed through maternal interviews. Maternal interviews also provided information about hospitalization or medical treatment of infants for asthma, eczema, other allergic diseases, otitis media, febrile seizures, respiratory syncytial virus infection, and other diseases from birth to the age of 18 months. A modified version of the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was administered. Development of allergies or infections in infants was defined as having had a doctor&rsquos diagnosis, hospitalization, or medical treatment between birth and the age of 18 months. Asthma was expanded to include cases in which the mother gave positive responses to all questions on the modified ISAAC questionnaire. There were no associations between maternal exposure and childhood food allergy, eczema, or asthma, although there was a weak positive trend of increased risk of asthma with increasing exposure to PCDFs (p = 0.059). There was also a weak positive association of third trimester PCDF concentrations and increased risk of otitis media (overall trend p = 0.027) compared with the children of women in the lowest quartile of exposure, the children of those in the highest quartile had 2.5 times the risk of having a confirmed case of otitis media (95% CI 1.07&ndash5.88) in multivariate adjusted models. The effect was more pronounced in male infants, who showed an indication of a dose&ndashresponse relationship, with an increase in risk in the highest quartile for dioxin activity from furans (OR = 3.80, 95% CI 1.09&ndash13.18) and for total dioxin activity (OR = 4.44, 95% CI 1.20&ndash16.45). There were also significant congener-specific associations with otitis media for octachlorodienzo-p-dioxin (OCDD) (all quartiles relative to the 1st quartile), 2,3,4,7,8-pentachlorodibenzofuran (4th quartile relative to 1st quartile), dioxin-like non-ortho PCB 77 (4th quartile relative to 1st quartile), and dioxin-like

mono-ortho PCB 157 (2nd quartile and 4th quartile relative to 1st quartile). Those findings provide some support for immunotoxic effects of dioxin-like compounds when the mother is exposed.

Jusko et al. (2011) reported on PCB exposures in Eastern Slovakia, examining concentrations in maternal and cord serum and immunoglobulin concentrations in offspring. No association between immunoglobulin concentrations and exposure was noted.

Offspring Reproductive Function

Since Update 2010, there have been three epidemiologic studies of maternal or perinatal exposure to dioxins and dioxin-like PCBs in relation to child reproductive development. Humblet et al. (2011) examined the association with maternal dioxin exposure in the highly-contaminated region of Chapaevsk, Russia, which until 2003 was the site of chlorinated-chemical production at the Middle Volga Chemical Plant. A mother&rsquos serum concentration 8&ndash9 years after pregnancy served as a surrogate measure of her son&rsquos in utero and lactational exposure. The study investigated 444 mother-son pairs (89% of the 499 peripubertal boys in the entire cohort) that were recruited when the boys were 8&ndash9 years old by using the townwide health-insurance information system in 2003&ndash2005. At study entry, a physical examination was conducted on each boy, maternal and child blood samples were drawn for measurement of TEQs and total PCB concentrations, and an extensive interview was administered. One of the study investigators (blinded to the subjects&rsquo dioxin concentrations) conducted all pubertal staging at study entry and annually thereafter. A carefully-considered covariate adjustment plan was implemented in this high-quality study. No association of maternal serum total TEQs was seen in any of the three indexes of pubertal onset measured. In a subset of boys who breastfed for at least 6 months, a dose-related delay (relative to those who breastfed less) in pubertal onset was seen with increasing quartiles of maternal TEQs. Overall, the study does not provide particularly strong or consistent evidence of an association between perinatal TEQ exposure and pubertal onset among boys.

Reproductive function in sons was also investigated by Mocarelli et al. (2011) 78 men 18&ndash26 years old who were born to women living in the most dioxin-polluted areas near Seveso, Italy, were eligible for the study. After refusals and exclusion for varicoceles, only 39 subjects (50%) remained, but previously-gathered information on all the mothers demonstrated that nonparticipation was not associated with the mothers&rsquo serum concentrations or with whether the sons were breastfed. Of the 39, 21 were breastfed (and so received both in utero and postnatal exposure via their mothers), and 18 were formula-fed (and so received only in utero exposure from their mothers). At-home semen samples were collected from the sons and graded according to the WHO (WHO, 1999) recommendations. At the same visit, fasting blood samples were obtained, and

they were measured for follicle-stimulating hormone (FSH), inhibin B, serum 17-&beta-estradiol, luteinizing hormone, and testosterone. Maternal serum TCDD measurements were taken from maternal serum frozen since 1976&ndash1977. Of consecutive blood donors, 123 men matched for age and socioeconomic status whose mothers had not resided in the contaminated area were asked to be controls, and 58 (47%) participated. Hormone data were adjusted for body mass index (BMI), smoking behavior, age at the time of test, chemical exposure, and alcohol use. Sperm-function models were also adjusted for educational level, employment status, and abstinence time. Seveso-exposed men had a lower adjusted mean sperm concentration than the comparison population (46.2 × 10 6 /mL vs 81.0 × 10 6 /mL, p = 0.01), lower total sperm count (139.2 × 10 6 vs 229.9 × 10 6 p = 0.03), and lower progressive motile sperm count (50.6 × 10 6 vs 90.5 × 10 6 p = 0.05). These and other associations (sperm progressive motility, FSH, and inhibin B) appeared to be substantially modified by whether the man had been breastfed in childhood the effects were strongest in, and to some degree limited to, men who had been breastfed. This indicates that early-life exposure via breast milk had more of an impact on these fertility-related outcomes in the later lives of the sons than did in utero exposure, but breastfeeding is a relevant mode of maternal exposure for the children of female Vietnam veterans. Those results suggest an effect of early-life exposure on adult reproductive function. Their reliability depends on the assumption that the Seveso-exposed and comparison populations are similar on all factors other than exposure, but the data provided indicate moderate differences in the sons&rsquo ages and duration of breastfeeding, while the covariate data provided are too limited for a full evaluation of the similarity of the groups. The results might have been enhanced by analyses using the mothers&rsquo measured dioxin concentrations.

Finally, Su et al. (2012) followed up 56 children (23 boys and 33 girls) from the Taiwanese mother-child birth cohort previously described (Chao et al., 2004 Wang et al., 2004, 2005). Children were stratified into low and high median placental PCDD, PCDF, and PCB exposure groups according to their mother&rsquos overall median exposure. The children&rsquos 8-hour fasting blood samples were obtained at followup and analyzed for testosterone, estradiol, luteinizing hormone, FSH, triglyceride, cholesterol, and insulin. There were few associations overall between dioxins and dioxin-like PCBs and hormone concentrations, other than higher median estradiol concentrations (3.0 ng/dL vs 1.8 ng/dL) in children whose mothers had lower total TEQs than in children whose mothers had higher total TEQs (p = 0.003). However, the comparisons were not adjusted for plausible confounders.

As reported in Update 2010, results of studies in rodent models provide support for the idea that prenatal exposure to TCDD can result in adverse effects in

offspring later in life, including immune disorders, behavioral disturbances, reproductive impairment, kidney disease, and cancers (Foster et al., 2011 Prescott, 2011 Puga, 2011 Takeda et al., 2012). Results of several new studies also support the idea. Using two mouse models, investigators showed that prenatal TCDD (2.5&ndash5.0 mg/kg of body weight) modified multiple immune signatures in adult offspring that were indicative of adult-onset autoimmunity (Holladay et al., 2011). Adult-onset inflammatory disease and lupus-like autoimmunity were also observed in mice at 36 weeks of age after high-dose prenatal TCDD exposures (Mustafa et al., 2011). A single prenatal exposure of rats to TCDD (0.7 &mug/kg of body weight) reduced brain developmental myelination and compromised remyelination potential in adults (Fernández et al., 2010), and in utero TCDD in mice alters neural progenitor differentiation (Mitsuhashi et al., 2010). However, a recent study suggested that, unlike murine neurospheres (which represent neural progenitor cells), human neurospheres were nonresponsive to TCDD because of lack of the AHR receptor&mdashan indication of species specificity in response (Gassmann et al., 2010). Perinatal TCDD (0.2&ndash0.4 &mug/kg of body weight) in rats perturbed neuroendocrine function as measured by thyrotropin and growth hormone concentrations in exposed offspring through peripubertal postnatal day 30, and this supports the idea of continued later-life thyroid hormone disturbances (Ahmed, 2011). As discussed below, a few animal studies have provided evidence of transmission of adverse effects to later generations.

Mechanisms that could underlie later-life effects in offspring and effects in later generations (transgenerational inheritance) could involve epigenetic processes as described at the beginning of this chapter. Research into dioxin&rsquos potential as an epigenetic agent is in its early stages, but a few studies have suggested that dioxin has such properties. Direct evidence, however, is limited to maternal exposures of the developing embryo or fetus during in utero growth, and there have been no reports on paternal TCDD exposure and later-life effects in offspring or paternally-mediated transgenerational effects. As reported in Update 2010, Wu et al. (2004) demonstrated that TCDD exposure of mouse embryos before implantation in unexposed females resulted in epigenetic changes, including increased methylation and reduced expression of imprinted genes, which implied that early embryonic exposure alone was sufficient to alter gene expression in the resulting offspring. Transmission of effects to later generations would involve epigenetic alterations in the developing germ cells of a fetus that was directly exposed to maternal TCDD in utero. The germ-line epigenome modified either through altered DNA methylation or through core histone modifications would be permanent (that is, would escape the normal erasure of an imprinted gene) and would be transmitted over several generations.

Results of a few recent studies support a transgenerational inheritance due to in utero exposure to TCDD. Exposure of pregnant mice to TCDD (at 10 &mug/kg) reduced fertility and increased premature birth in three later generations (Bruner-Tran and Osteen, 2011) effects were transmitted through both male and

female offspring (Ding et al., 2011 McConaha et al., 2011). Exposure of gestating female rats (F0) to dioxin (TCDD) at 100 ng/kg was recently shown to result in earlier puberty in the offspring (F1) and two later generations (F2 and F3) and to reduce ovarian follicle numbers in females of the F3 generation this implies transgenerational inheritance (Manikkam et al., 2012a). The F3 effects appear to be transmitted through the sperm that were initially exposed to maternal dioxin in utero. In a second paper by the same research team, additional diseases appeared later in life in the first generation (directly-exposed offspring), including prostate disease in males and ovarian follicle loss and polycystic ovarian disease in females (Manikkan et al., 2012b). Further third-generation effects were noted, including kidney disease in males and polycystic ovarian disease in females, and imply transgenerational inheritance. The latter appear to be transmitted through the sperm originally exposed to maternal dioxin in utero inasmuch as sperm DNA methylation changes were observed at 50 chromosomal sites in generations F1&ndashF3.

Another mode of epigenetic change is modification of the spatial arrangement of chromosomes, which can influence gene expression and cell differentiation. Oikawa et al. (2008) have found that TCDD, through the AHR, modifies the positions of chromosomes in the interphase nuclei of human preadipocytes.

The studies discussed above suggest that TCDD has the potential to influence the epigenome and therefore could promote changes in offspring that lead to disease later in life.

The epidemiologic studies designed to examine effects of the COIs in more-mature offspring have evaluated a variety of biomarkers pertaining to the neurologic, immunologic, and endocrine systems. Most have not examined defined clinical conditions, although data on associations with otitis media (Miyashita et al., 2011 Weisglas-Kuperus et al., 2000) and impaired fertility in adult sons of exposed females (Mocarelli et al., 2011) are emerging. More studies that examine those and other end points are required. In particular, it would be of interest to obtain information on neuropsychiatric conditions in children who were exposed in utero, such as attention-deficit hyperactivity disorder and other clinically-defined neurodevelopmental outcomes. The animal literature contains evidence that environmental agents mediated by maternal exposure affect later generations through fetal and germ-line modifications, but, in the case of adult male exposures before conception of the next generation, there is insufficient evidence of transgenerational affects.

There is inadequate or insufficient evidence to determine whether there is an association between exposure of men and women to 2,4-D, 2,4,5-T, TCDD, picloram, or cacodylic acid before conception or during pregnancy and disease in their children as they mature or in later generations. Although results of laboratory research support the plausibility of transgenerational clinical conditions, the body of human data is insufficient to support an association between the COIs and such disease states in human offspring.

ACS (American Cancer Society). 2010. Cancer Facts and Figures 2010. http://www.cancer.org/acs/groups/content/@nho/documents/document/acspc-024113.pdf (accessed May 16, 2011).

ACS. 2013. Cancer Facts and Figures 2013. Atlanta, GA: American Cancer Society.

ADVA (Australia Department of Veterans Affairs). 1983. Case-Control Study of Congenital Anomalies and Vietnam Service. Canberra, Australia: ADVA.

Ahmed RG. 2011. Perinatal TCDD exposure alters developmental neuroendocrine system. Food and Chemical Toxicology 49:1276&ndash1284.

AIHW (Australian Institute of Health and Welfare). 1999. Morbidity of Vietnam Veterans: A Study of the Health of Australia&rsquos Vietnam Veteran Community: Volume 3: Validation Study. Canberra, Australia.

AIHW. 2000. Morbidity of Vietnam Veterans. Adrenal Gland Cancer, Leukaemia and Non-Hodgkin&rsquos Lymphoma: Supplementary Report No. 2. (AIHW cat. no. PHE 28). Canberra, Australia: AIHW. AIHW. 2001. Morbidity of Vietnam Veterans. Adrenal Gland Cancer, Leukaemia and Non-Hodgkin&rsquos Lymphoma: Supplementary Report No. 2. Revised edition (AIHW cat. No. PHE 34). Canberra, Australia: AIHW.

Aschengrau A, Monson RR. 1990. Paternal military service in Vietnam and the risk of late adverse pregnancy outcomes. American Journal of Public Health 80(10):1218&ndash1224.

Barker DJP, Lampl M, Roseboom T, Winder N. 2012. Resource allocation in utero and health in later life. Placenta 33:e30&ndashe34.

Bertazzi PA, Zocchetti C, Pesatori AC, Guercilena S, Consonni D, Tironi A, Landi MT. 1992. Mortality of a young population after accidental exposure to 2,3,7,8-tetrachlorodibenzodioxin. International Journal of Epidemiology 21(1):118&ndash123.

Blatter BM, Hermens R, Bakker M, Roeleveld N, Verbeek AL, Zielhuis GA. 1997. Paternal occupational exposure around conception and spina bifida in offspring. American Journal of Industrial Medicine 32(3):283&ndash291.

Bloom AD, ed. 1981. Guidelines for Studies of Human Populations Exposed to Mutagenic and Reproductive Hazards. White Plains, NY: March of Dimes Foundation.

Brown NM, Manzolillo PA, Zhang JX, Wang J, Lamartiniere CA. 1998. Prenatal TCDD and predisposition to mammary cancer in the rat. Carcinogenesis 19(9):1623&ndash1629.

Bruner-Tran KL, Osteen KG. 2011. Developmental exposure to TCDD reduces fertility and negatively affects pregnancy outcomes across multiple generations. Reproductive Toxicology 31:344&ndash350.

1 Throughout this report, the same alphabetic indicator after year of publication is used consistently for a given reference when there are multiple citations by the same first author in a given year. The convention of assigning the alphabetic indicators in order of citation in a given chapter is not followed.

Buckley JD, Robison LL, Swotinsky R, Garabrant DH, LeBeau M, Manchester P, Nesbit ME, Odom L, Peters JM, Woods WG, Hammond GD. 1989. Occupational exposures of parents of children with acute nonlymphocytic leukemia: A report from the Childrens&rsquo Cancer Study Group. Cancer Research 49(14):4030&ndash4037.

CDC (Centers for Disease Control and Prevention). 1989a. Health Status of Vietnam Veterans. Vietnam Experience Study, Vol. V Reproductive Outcomes and Child Health. Atlanta, GA: US Department of Health and Human Services.

CDC. 1989b. Health Status of Vietnam Veterans. Vietnam Experience Study, Vol. V Reproductive Outcomes and Child Health. Atlanta, GA: US Department of Health and Human Services.

Chao HR, Wang SL, Lee CC, Yu HY, Lu YK, Päpke O. 2004. Level of polychlorinated dibenzo-p-dioxins, dibenzofurans and biphenyls (PCDD/Fs, PCBs) in human milk and the input to infant body burden. Food and Chemical Toxicology 42:1299&ndash1308.

Chapin RE, Robbins WA, Schieve LA, Sweeney AM, Tabacova SA, Tomashek KM. 2004. Off to a good start: The influence of pre- and periconceptional exposures, parental fertility, and nutrition on children&rsquos health. Environmental Health Perspectives 112(1):69&ndash78.

Chen Z, Stewart PA, Davies S, Giller R, Krailo M, Davis M, Robison L, Shu XO. 2005. Parental occupational exposure to pesticides and childhood germ-cell tumors. American Journal of Epidemiology 162(9):858&ndash867.

Chen Z, Robison L, Giller R, Krailo M, Davis M, Davies S, Shu XO. 2006. Environmental exposure to residential pesticides, chemicals, dusts, fumes, and metals, and risk of childhood germ cell tumors. International Journal of Hygiene and Environmental Health 209(1):31&ndash40.

Chia SE, Shi LM. 2002. Review of recent epidemiological studies on paternal occupations and birth defects. Occupational and Environmental Medicine 59(3):149&ndash155.

Chokkalingam AP, Metayer C, Scelo GA, Chang JS, Urayama KY, Aldrich MC, Guha N, Hansen HM, Dahl GV, Barcellos LF, Wiencke JK, Wiemels JL, Buffler PA. 2012. Variation in xenobiotic transport and metabolism genes, household chemical exposures, and risk of childhood acute lymphoblastic leukemia. Cancer Causes and Control 23(8):1367&ndash1375.

Chow EJ, Kamineni A, Daling, JR, Fraser A, Wiggins CL, Mineau GP, Hamre MR, Severson RK, Drews-Botsch C, Mueller BA. 2009. Reproductive outcomes in male cancer survivors: A linked cancer-birth registry analysis. Archives of Pediatric and Adolescent Medicine 163(10):887&ndash894.

Codrington AM, Hales BF, Robaire B. 2004. Spermiogenic germ cell phase-specific DNA damage following cyclophosphamide exposure. Journal of Andrology 25(3):354&ndash362.

Cooney MA, Daniels JL, Ross JA, Breslow NE, Pollock BH, Olshan AF. 2007. Household pesticides and the risk of Wilms tumor. Environmental Health Perspectives 115(1):134&ndash137.

Cordier S, Chevrier C, Robert-Gnansia E, Lorente C, Brula P, Hours M. 2004. Risk of congenital anomalies in the vicinity of municipal solid waste incinerators. Occupational and Environmental Medicine 61(1):8&ndash15.

Cordier S, Lehebel A, Amar E, Anzivino-Viricel L, Hours M, Monfort C, Chevrier C, Chiron M, Robert-Gnansia E. 2010. Maternal residence near municipal waste incinerators and the risk of urinary tract birth defects. Occupational and Environmental Medicine 67(7):493&ndash499.

Daniels JL, Olshan AF, Teschke K, Herz-Picciotto I, Savitz DA, Blatt J, Bondy ML, Neglia JP, Pollock BH, Cohn SL, Look AT, Seeger RC, Castleberry RP. 2001. Residential pesticide exposure and neuroblastoma. Epidemiology 12:20&ndash27.

De Roos AJ, Olshan AF, Teschke K, Poole C, Savitz DA, Blatt J, Bondy ML, Pollock BH. 2001a. Parental occupational exposures to chemicals and incidence of neuroblastoma in offspring. American Journal of Epidemiology 154(2):106&ndash114.

De Roos AJ, Teschke K, Savitz DA, Poole C, Grufferman S, Pollock BH, Olshan AF. 2001b. Parental occupational exposures to electromagnetic fields and radiation and incidence of neuroblastoma in offspring. Epidemiology 12(5):508&ndash517.


Short-term prediction of glucose in type 1 diabetes using kernel adaptive filters

This study aims at presenting a nonlinear, recursive, multivariate prediction model of the subcutaneous glucose concentration in type 1 diabetes. Nonlinear regression is performed in a reproducing kernel Hilbert space, by either the fixed budget quantized kernel least mean square (QKLMS-FB) or the approximate linear dependency kernel recursive least-squares (KRLS-ALD) algorithm, such that a sparse model structure is accomplished. A multivariate feature set (i.e., subcutaneous glucose, food carbohydrates, insulin regime and physical activity) is used and its influence on short-term glucose prediction is investigated. The method is evaluated using data from 15 patients with type 1 diabetes in free-living conditions. In the case when all the input variables are considered: (i) the average root mean squared error (RMSE) of QKLMS-FB increases from 13.1 mg dL −1 (mean absolute percentage error (MAPE) 6.6%) for a 15-min prediction horizon (PH) to 37.7 mg dL −1 (MAPE 20.8%) for a 60-min PH and (ii) the RMSE of KRLS-ALD, being predictably lower, increases from 10.5 mg dL −1 (MAPE 5.2%) for a 15-min PH to 31.8 mg dL −1 (MAPE 18.0%) for a 60-min PH. Multivariate data improve systematically both the regularity and the time lag of the predictions, reducing the errors in critical glucose value regions for a PH ≥ 30 min.

This is a preview of subscription content, access via your institution.


Chapter 11 Bayesian Networks

A Bayesian network is a tool for modeling and reasoning with uncertain beliefs it comprises two parts: a qualitative component in the form of a directed acyclic graph (DAG) and a quantitative component in the form conditional probabilities. Intuitively, the DAG of a Bayesian network explicates variables of interest (DAG nodes) and the direct influences among them (DAG edges). The conditional probabilities of a Bayesian network quantify the dependencies between variables and their parents in the DAG. Formally though, a Bayesian network is interpreted as specifying a unique probability distribution over its variables. Hence, the network can be viewed as a factored (compact) representation of an exponentially sized probability distribution. The formal syntax and semantics of Bayesian networks are discussed in this chapter. The power of Bayesian networks as a representational tool stems both from the ability to represent large probability distributions compactly and the availability of inference algorithms to answer queries about these distributions without necessarily constructing them explicitly. The chapter also discusses exact inference algorithms and approximate inference algorithms.


The Study of Intermolecular Potentials with Molecular Beams at Thermal Energies

Attractive forces of different orders of magnitude can occur between two neutral atoms or molecules. If the electron spins of two approaching atoms are parallel or if one or both of the partners are rare gas atoms, or molecules for which chemical bonding is not possible, only an extremely weak attractive potential is observed. This potential has a maximum depth of only 10 ˉ 3 to10 ˉ 1 eV and extends out to distances of about > 10 Å, which is large compared with the gas kinetic radius of the partners this phenomena is called the van der Waals potential. If, on the other hand, the two atoms can form a stable molecule (antiparallel electron spins), an extremely strong attractive potential appears at smaller distances of approach. A strong attractive potential may also appear if an atom or molecule reacts with another molecule. In both instances, the potential may have a depth of several electron volts, corresponding to, in the case of two atoms, the dissociation energy of the stable molecule. This is called the chemical potential. If chemical forces exist, the van der Waals potential are observable only at very large separations. At very close distances of approach, these attractive potentials are more than compensated for by an extremely strong rapidly rising repulsive potential. Moreover, in the interaction of two atoms, the quantum mechanical dispersion force is largely responsible for the attractive potential. This potential comes about due to the mutual perturbation of the electrons in the two atomic systems.


Abstract

In this paper, we report on a two-scale approach for efficient matrix-free finite element simulations. It is an extended version of our previous conference publication [1]. The proposed method is based on surrogate element matrices constructed by low order polynomial approximations. It is applied to a Stokes-type PDE system with variable viscosity as is a key component in mantle convection models. We set the ground for a rigorous performance analysis inspired by the concept of parallel textbook multigrid efficiency and study the weak scaling behavior on SuperMUC, a peta-scale supercomputer system. For a complex geodynamical model, we achieve, on up to 47 250 compute cores, a parallel efficiency of 93% for application of the discrete operator and 83% for a complete Uzawa V-cycle including the coarse grid solve. Our largest simulation uses a trillion ( O ( 10 12 ) ) degrees of freedom for a global mesh resolution of 1.5 km. Applicability of our new approach for geodynamical problems is demonstrated by investigating dynamic topography for classical benchmark settings as well as for high-resolution models with lateral viscosity variations.


Deitel.Java. How to Program.9th Edition.2012

Book Details:
Deitel, Paul J.
Java : how to program / P.J. Deitel, H.M. Deitel. -- 9th ed.
p. cm.
H.M. Deitel's name appears on the earlier editions.
Includes index.
ISBN 978-0-13-257566-9
ISBN-10: 0-13-257566-3
Copyright�

About the Book
Live in fragments no longer, only connect.
—Edgar Morgan Foster

Welcome to Java and Java How to Program, Ninth Edition! This book presents leadingedge computing technologies for students, instructors and software developers.
The new Chapter 1 engages students with intriguing facts and figures to get them excited about studying computers and programming. The chapter includes a table of some of the research made possible by computers current technology trends and hardware discussion the data hierarchy a table of mobile and Internet app platforms a new section on social networking an introduction to Android a table of popular web services a table of business and technology publications and websites that will help you stay up to date with the latest technology news and trends and updated exercises.
The book is appropriate for introductory course sequences based on the ACM/IEEE curriculum recommendations and for AP Computer Science exam preparation.
We focus on software engineering best practices. At the heart of the book is the Deitel signature “live-code approach”—concepts are presented in the context of complete working programs, rather than in code snippets. Each complete code example is accompanied by live sample executions. All the source code is available at www.deitel.com/books/jhtp9/ and at the book’s Companion Website www.pearsonhighered.com/deitel/.
As you read the book, if you have questions, send an e-mail to [email protected] we’ll respond promptly. For updates on this book, visit www.deitel.com/books/jhtp9/, follow us on Facebook (www.deitel.com/deitelfan) and Twitter (@deitel), and subscribe to the Deitel® Buzz Online newsletter (www.deitel.com/newsletter/subscribe.html).

Table of Contents

Preface xxiii
Before You Begin xxxiii
1 Introduction to Computers and Java 1
1.1 Introduction 2
1.2 Computers: Hardware and Software 5
1.3 Data Hierarchy 6
1.4 Computer Organization 8
1.5 Machine Languages, Assembly Languages and High-Level Languages 10
1.6 Introduction to Object Technology 11
1.7 Operating Systems 13
1.8 Programming Languages 16
1.9 Java and a Typical Java Development Environment 18
1.10 Test-Driving a Java Application 22
1.11 Web 2.0: Going Social 26
1.12 Software Technologies 29
1.13 Keeping Up-to-Date with Information Technologies 31
1.14 Wrap-Up 32

2 Introduction to Java Applications 37
2.1 Introduction 38
2.2 Your First Program in Java: Printing a Line of Text 38
2.3 Modifying Your First Java Program 44
2.4 Displaying Text with printf 46
2.5 Another Application: Adding Integers 47
2.6 Memory Concepts 52
2.7 Arithmetic 53
2.8 Decision Making: Equality and Relational Operators 56
2.9 Wrap-Up 60

3 Introduction to Classes, Objects, Methods and Strings 71
3.1 Introduction 72
3.2 Declaring a Class with a Method and Instantiating an Object of a Class 72
3.3 Declaring a Method with a Parameter 76
3.4 Instance Variables, set Methods and get Methods 79
3.5 Primitive Types vs. Reference Types 84
3.6 Initializing Objects with Constructors 85
3.7 Floating-Point Numbers and Type double 88
3.8 (Optional) GUI and Graphics Case Study: Using Dialog Boxes 92
3.9 Wrap-Up 95

4 Control Statements: Part 1 102
4.1 Introduction 103
4.2 Algorithms 103
4.3 Pseudocode 104
4.4 Control Structures 104
4.5 if Single-Selection Statement 107
4.6 if…else Double-Selection Statement 107
4.7 while Repetition Statement 112
4.8 Formulating Algorithms: Counter-Controlled Repetition 113
4.9 Formulating Algorithms: Sentinel-Controlled Repetition 118
4.10 Formulating Algorithms: Nested Control Statements 125
4.11 Compound Assignment Operators 130
4.12 Increment and Decrement Operators 130
4.13 Primitive Types 134
4.14 (Optional) GUI and Graphics Case Study: Creating Simple Drawings 134
4.15 Wrap-Up 138

5 Control Statements: Part 2 151
5.1 Introduction 152
5.2 Essentials of Counter-Controlled Repetition 152
5.3 for Repetition Statement 154
5.4 Examples Using the for Statement 158
5.5 do…while Repetition Statement 162
5.6 switch Multiple-Selection Statement 164
5.7 break and continue Statements 172
5.8 Logical Operators 173
5.9 Structured Programming Summary 179
5.10 (Optional) GUI and Graphics Case Study: Drawing Rectangles and Ovals 184
5.11 Wrap-Up 187

6 Methods: A Deeper Look 197
6.1 Introduction 198
6.2 Program Modules in Java 198
6.3 static Methods, static Fields and Class Math 200
6.4 Declaring Methods with Multiple Parameters 202
6.5 Notes on Declaring and Using Methods 205
6.6 Method-Call Stack and Activation Records 206
6.7 Argument Promotion and Casting 207
6.8 Java API Packages 208
6.9 Case Study: Random-Number Generation 210
6.9.1 Generalized Scaling and Shifting of Random Numbers 214
6.9.2 Random-Number Repeatability for Testing and Debugging 214
6.10 Case Study: A Game of Chance Introducing Enumerations 215
6.11 Scope of Declarations 219
6.12 Method Overloading 222
6.13 (Optional) GUI and Graphics Case Study: Colors and Filled Shapes 224
6.14 Wrap-Up 227

7 Arrays and ArrayLists 240
7.1 Introduction 241
7.2 Arrays 242
7.3 Declaring and Creating Arrays 243
7.4 Examples Using Arrays 244
7.5 Case Study: Card Shuffling and Dealing Simulation 254
7.6 Enhanced for Statement 258
7.7 Passing Arrays to Methods 259
7.8 Case Study: Class GradeBook Using an Array to Store Grades 262
7.9 Multidimensional Arrays 268
7.10 Case Study: Class GradeBook Using a Two-Dimensional Array 271
7.11 Variable-Length Argument Lists 278
7.12 Using Command-Line Arguments 279
7.13 Class Arrays 281
7.14 Introduction to Collections and Class ArrayList 284
7.15 (Optional) GUI and Graphics Case Study: Drawing Arcs 286
7.16 Wrap-Up 289

8 Classes and Objects: A Deeper Look 311
8.1 Introduction 312
8.2 Time Class Case Study 312
8.3 Controlling Access to Members 316
8.4 Referring to the Current Object’s Members with the this Reference 317
8.5 Time Class Case Study: Overloaded Constructors 320
8.6 Default and No-Argument Constructors 326
8.7 Notes on Set and Get Methods 326
8.8 Composition 328
8.9 Enumerations 331
8.10 Garbage Collection and Method finalize 333
8.11 static Class Members 334
8.12 static Import 338
8.13 final Instance Variables 339
8.14 Time Class Case Study: Creating Packages 340
8.15 Package Access 345
8.16 (Optional) GUI and Graphics Case Study: Using Objects with Graphics 347
8.17 Wrap-Up 351

9 Object-Oriented Programming: Inheritance 359
9.1 Introduction 360
9.2 Superclasses and Subclasses 361
9.3 protected Members 363
9.4 Relationship between Superclasses and Subclasses 364
9.4.1 Creating and Using a CommissionEmployee Class 364
9.4.2 Creating and Using a BasePlusCommissionEmployee Class 370
9.4.3 Creating a CommissionEmployee—BasePlusCommissionEmployee Inheritance Hierarchy 375
9.4.4 CommissionEmployee—BasePlusCommissionEmployee Inheritance Hierarchy Using protected Instance Variables 377
9.4.5 CommissionEmployee—BasePlusCommissionEmployee Inheritance Hierarchy Using private Instance Variables 380
9.5 Constructors in Subclasses 385
9.6 Software Engineering with Inheritance 386
9.7 Class Object 387
9.8 (Optional) GUI and Graphics Case Study: Displaying Text and Images Using Labels 388
9.9 Wrap-Up 391

10 Object-Oriented Programming: Polymorphism 394
10.1 Introduction 395
10.2 Polymorphism Examples 397
10.3 Demonstrating Polymorphic Behavior 398
10.4 Abstract Classes and Methods 400
10.5 Case Study: Payroll System Using Polymorphism 403
10.5.1 Abstract Superclass Employee 404
10.5.2 Concrete Subclass SalariedEmployee 407
10.5.3 Concrete Subclass HourlyEmployee 408
10.5.4 Concrete Subclass CommissionEmployee 410
10.5.5 Indirect Concrete Subclass BasePlusCommissionEmployee 412
10.5.6 Polymorphic Processing, Operator instanceof and Downcasting 413
10.5.7 Summary of the Allowed Assignments Between Superclass and Subclass Variables 418
10.6 final Methods and Classes 418
10.7 Case Study: Creating and Using Interfaces 419
10.7.1 Developing a Payable Hierarchy 421
10.7.2 Interface Payable 422
10.7.3 Class Invoice 422
10.7.4 Modifying Class Employee to Implement Interface Payable 425
10.7.5 Modifying Class SalariedEmployee for Use in the Payable Hierarchy 427
10.7.6 Using Interface Payable to Process Invoices and Employees Polymorphically 428
10.7.7 Common Interfaces of the Java API 430
10.8 (Optional) GUI and Graphics Case Study: Drawing with Polymorphism 431
10.9 Wrap-Up 433

11 Exception Handling: A Deeper Look 438
11.1 Introduction 439
11.2 Example: Divide by Zero without Exception Handling 439
11.3 Example: Handling ArithmeticExceptions and InputMismatchExceptions 442
11.4 When to Use Exception Handling 447
11.5 Java Exception Hierarchy 447
11.6 finally Block 450
11.7 Stack Unwinding and Obtaining Information from an Exception Object 454
11.8 Chained Exceptions 457
11.9 Declaring New Exception Types 459
11.10 Preconditions and Postconditions 460
11.11 Assertions 461
11.12 (New in Java SE 7) Multi-catch: Handling Multiple Exceptions in One catch 462
11.13 (New in Java SE 7) try-with-Resources: Automatic Resource Deallocation 463
11.14 Wrap-Up 463

12 ATM Case Study, Part 1: Object-Oriented Design with the UML 469
12.1 Case Study Introduction 470
12.2 Examining the Requirements Document 470
12.3 Identifying the Classes in a Requirements Document 478
12.4 Identifying Class Attributes 484
12.5 Identifying Objects’ States and Activities 489
12.6 Identifying Class Operations 493
12.7 Indicating Collaboration Among Objects 499
12.8 Wrap-Up 506

13 ATM Case Study Part 2: Implementing an Object-Oriented Design 510
13.1 Introduction 511
13.2 Starting to Program the Classes of the ATM System 511
13.3 Incorporating Inheritance and Polymorphism into the ATM System 516
13.4 ATM Case Study Implementation 522
13.4.1 Class ATM 523
13.4.2 Class Screen 528
13.4.3 Class Keypad 529
13.4.4 Class CashDispenser 530
13.4.5 Class DepositSlot 531
13.4.6 Class Account 532
13.4.7 Class BankDatabase 534
13.4.8 Class Transaction 537
13.4.9 Class BalanceInquiry 538
13.4.10 Class Withdrawal 539
13.4.11 Class Deposit 543
13.4.12 Class ATMCaseStudy 546
13.5 Wrap-Up 546

14 GUI Components: Part 1 549
14.1 Introduction 550
14.2 Java’s New Nimbus Look-and-Feel 551
14.3 Simple GUI-Based Input/Output with JOptionPane 552
14.4 Overview of Swing Components 555
14.5 Displaying Text and Images in a Window 557
14.6 Text Fields and an Introduction to Event Handling with Nested Classes 561
14.7 Common GUI Event Types and Listener Interfaces 567
14.8 How Event Handling Works 569
14.9 JButton 571
14.10 Buttons That Maintain State 574
14.10.1 JCheckBox 574
14.10.2 JRadioButton 577
14.11 JComboBox Using an Anonymous Inner Class for Event Handling 580
14.12 JList 584
14.13 Multiple-Selection Lists 586
14.14 Mouse Event Handling 589
14.15 Adapter Classes 594
14.16 JPanel Subclass for Drawing with the Mouse 597
14.17 Key Event Handling 601
14.18 Introduction to Layout Managers 604
14.18.1 FlowLayout 605
14.18.2 BorderLayout 608
14.18.3 GridLayout 611
14.19 Using Panels to Manage More Complex Layouts 613
14.20 JTextArea 615
14.21 Wrap-Up 618

15 Graphics and Java 2D 631
15.1 Introduction 632
15.2 Graphics Contexts and Graphics Objects 634
15.3 Color Control 635
15.4 Manipulating Fonts 642
15.5 Drawing Lines, Rectangles and Ovals 647
15.6 Drawing Arcs 651
15.7 Drawing Polygons and Polylines 654
15.8 Java 2D API 657
15.9 Wrap-Up 664

16 Strings, Characters and Regular Expressions 672
16.1 Introduction 673
16.2 Fundamentals of Characters and Strings 673
16.3 Class String 674
16.3.1 String Constructors 674
16.3.2 String Methods length, charAt and getChars 675
16.3.3 Comparing Strings 676
16.3.4 Locating Characters and Substrings in Strings 681
16.3.5 Extracting Substrings from Strings 683
16.3.6 Concatenating Strings 684
16.3.7 Miscellaneous String Methods 684
16.3.8 String Method valueOf 686
16.4 Class StringBuilder 687
16.4.1 StringBuilder Constructors 688
16.4.2 StringBuilder Methods length, capacity, setLength and ensureCapacity 688
16.4.3 StringBuilder Methods charAt, setCharAt, getChars and reverse 690
16.4.4 StringBuilder append Methods 691
16.4.5 StringBuilder Insertion and Deletion Methods 693
16.5 Class Character 694
16.6 Tokenizing Strings 699
16.7 Regular Expressions, Class Pattern and Class Matcher 700
16.8 Wrap-Up 708

17 Files, Streams and Object Serialization 719
17.1 Introduction 720
17.2 Files and Streams 720
17.3 Class File 722
17.4 Sequential-Access Text Files 726
17.4.1 Creating a Sequential-Access Text File 726
17.4.2 Reading Data from a Sequential-Access Text File 733
17.4.3 Case Study: A Credit-Inquiry Program 736
17.4.4 Updating Sequential-Access Files 741
17.5 Object Serialization 742
17.5.1 Creating a Sequential-Access File Using Object Serialization 743
17.5.2 Reading and Deserializing Data from a Sequential-Access File 749
17.6 Additional java.io Classes 751
17.6.1 Interfaces and Classes for Byte-Based Input and Output 751
17.6.2 Interfaces and Classes for Character-Based Input and Output 753
17.7 Opening Files with JFileChooser 754
17.8 Wrap-Up 757

18 Recursion 765
18.1 Introduction 766
18.2 Recursion Concepts 767
18.3 Example Using Recursion: Factorials 768
18.4 Example Using Recursion: Fibonacci Series 771
18.5 Recursion and the Method-Call Stack 774
18.6 Recursion vs. Iteration 776
18.7 Towers of Hanoi 777
18.8 Fractals 779
18.9 Recursive Backtracking 790
18.10 Wrap-Up 790

19 Searching, Sorting and Big O 798
19.1 Introduction 799
19.2 Searching Algorithms 800
19.2.1 Linear Search 800
19.2.2 Binary Search 804
19.3 Sorting Algorithms 809
19.3.1 Selection Sort 810
19.3.2 Insertion Sort 814
19.3.3 Merge Sort 817
19.4 Wrap-Up 824

20 Generic Collections 829
20.1 Introduction 830
20.2 Collections Overview 830
20.3 Type-Wrapper Classes for Primitive Types 831
20.4 Autoboxing and Auto-Unboxing 832
20.5 Interface Collection and Class Collections 832
20.6 Lists 833
20.6.1 ArrayList and Iterator 834
20.6.2 LinkedList 836
20.7 Collections Methods 841
20.7.1 Method sort 842
20.7.2 Method shuffle 845
20.7.3 Methods reverse, fill, copy, max and min 847
20.7.4 Method binarySearch 849
20.7.5 Methods addAll, frequency and disjoint 851
20.8 Stack Class of Package java.util 853
20.9 Class PriorityQueue and Interface Queue 855
20.10 Sets 856
20.11 Maps 859
20.12 Properties Class 863
20.13 Synchronized Collections 866
20.14 Unmodifiable Collections 866
20.15 Abstract Implementations 867
20.16 Wrap-Up 867

21 Generic Classes and Methods 873
21.1 Introduction 874
21.2 Motivation for Generic Methods 874
21.3 Generic Methods: Implementation and Compile-Time Translation 877
21.4 Additional Compile-Time Translation Issues: Methods That Use a Type Parameter as the Return Type 880
21.5 Overloading Generic Methods 883
21.6 Generic Classes 883
21.7 Raw Types 891
21.8 Wildcards in Methods That Accept Type Parameters 895
21.9 Generics and Inheritance: Notes 899
21.10 Wrap-Up 900

22 Custom Generic Data Structures 904
22.1 Introduction 905
22.2 Self-Referential Classes 905
22.3 Dynamic Memory Allocation 906
22.4 Linked Lists 907
22.5 Stacks 917
22.6 Queues 921
22.7 Trees 924
22.8 Wrap-Up 930

23 Applets and Java Web Start 941
23.1 Introduction 942
23.2 Sample Applets Provided with the JDK 943
23.3 Simple Java Applet: Drawing a String 947
23.3.1 Executing WelcomeApplet in the appletviewer 949
23.3.2 Executing an Applet in a Web Browser 951
23.4 Applet Life-Cycle Methods 951
23.5 Initialization with Method init 952
23.6 Sandbox Security Model 954
23.7 Java Web Start and the Java Network Launch Protocol (JNLP) 956
23.7.1 Packaging the DrawTest Applet for Use with Java Web Start 956
23.7.2 JNLP Document for the DrawTest Applet 957
23.8 Wrap-Up 961

24 Multimedia: Applets and Applications 967
24.1 Introduction 968
24.2 Loading, Displaying and Scaling Images 969
24.3 Animating a Series of Images 975
24.4 Image Maps 982
24.5 Loading and Playing Audio Clips 985
24.6 Playing Video and Other Media with Java Media Framework 988
24.7 Wrap-Up 992
24.8 Web Resources 992

25 GUI Components: Part 2 1000
25.1 Introduction 1001
25.2 JSlider 1001
25.3 Windows: Additional Notes 1005
25.4 Using Menus with Frames 1006
25.5 JPopupMenu 1014
25.6 Pluggable Look-and-Feel 1017
25.7 JDesktopPane and JInternalFrame 1022
25.8 JTabbedPane 1026
25.9 Layout Managers: BoxLayout and GridBagLayout 1028
25.10 Wrap-Up 1040

26 Multithreading 1045
26.1 Introduction 1046
26.2 Thread States: Life Cycle of a Thread 1048
26.3 Creating and Executing Threads with Executor Framework 1051
26.4 Thread Synchronization 1054
26.4.1 Unsynchronized Data Sharing 1055
26.4.2 Synchronized Data Sharing–Making Operations Atomic 1059
26.5 Producer/Consumer Relationship without Synchronization 1062
26.6 Producer/Consumer Relationship: ArrayBlockingQueue 1070
26.7 Producer/Consumer Relationship with Synchronization 1073
26.8 Producer/Consumer Relationship: Bounded Buffers 1079
26.9 Producer/Consumer Relationship: The Lock and Condition Interfaces 1086
26.10 Concurrent Collections Overview 1093
26.11 Multithreading with GUI 1095
26.11.1 Performing Computations in a Worker Thread 1096
26.11.2 Processing Intermediate Results with SwingWorker 1102
26.12 Interfaces Callable and Future 1109
26.13 Java SE 7: Fork/Join Framework 1109
26.14 Wrap-Up 1110

27 Networking 1118
27.1 Introduction 1119
27.2 Manipulating URLs 1120
27.3 Reading a File on a Web Server 1125
27.4 Establishing a Simple Server Using Stream Sockets 1128
27.5 Establishing a Simple Client Using Stream Sockets 1130
27.6 Client/Server Interaction with Stream Socket Connections 1130
27.7 Datagrams: Connectionless Client/Server Interaction 1142
27.8 Client/Server Tic-Tac-Toe Using a Multithreaded Server 1150
27.9 [Web Bonus] Case Study: DeitelMessenger 1165
27.10 Wrap-Up 1165

28 Accessing Databases with JDBC 1171
28.1 Introduction 1172
28.2 Relational Databases 1173
28.3 Relational Database Overview: The books Database 1174
28.4 SQL 1177
28.4.1 Basic SELECT Query 1178
28.4.2 WHERE Clause 1179
28.4.3 ORDER BY Clause 1181
28.4.4 Merging Data from Multiple Tables: INNER JOIN 1182
28.4.5 INSERT Statement 1184
28.4.6 UPDATE Statement 1185
28.4.7 DELETE Statement 1186
28.5 Instructions for Installing MySQL and MySQL Connector/J 1186
28.6 Instructions for Setting Up a MySQL User Account 1187
28.7 Creating Database books in MySQL 1188
28.8 Manipulating Databases with JDBC 1189
28.8.1 Connecting to and Querying a Database 1189
28.8.2 Querying the books Database 1194
28.9 RowSet Interface 1207
28.10 Java DB/Apache Derby 1209
28.11 PreparedStatements 1211
28.12 Stored Procedures 1226
28.13 Transaction Processing 1227
28.14 Wrap-Up 1227
28.15 Web Resources 1228

29 JavaServer™ Faces Web Apps: Part 1 1235
29.1 Introduction 1236
29.2 HyperText Transfer Protocol (HTTP) Transactions 1237
29.3 Multitier Application Architecture 1240
29.4 Your First JSF Web App 1241
29.4.1 The Default index.xhtml Document: Introducing Facelets 1242
29.4.2 Examining the WebTimeBean Class 1244
29.4.3 Building the WebTime JSF Web App in NetBeans 1246
29.5 Model-View-Controller Architecture of JSF Apps 1250
29.6 Common JSF Components 1250
29.7 Validation Using JSF Standard Validators 1254
29.8 Session Tracking 1261
29.8.1 Cookies 1262
29.8.2 Session Tracking with @SessionScoped Beans 1263
29.9 Wrap-Up 1269

30 JavaServer™ Faces Web Apps: Part 2 1276
30.1 Introduction 1277
30.2 Accessing Databases in Web Apps 1277
30.2.1 Setting Up the Database 1279
30.2.2 @ManagedBean Class AddressBean 1282
30.2.3 index.xhtml Facelets Page 1286
30.2.4 addentry.xhtml Facelets Page 1288
30.3 Ajax 1290
30.4 Adding Ajax Functionality to the Validation App 1292
30.5 Wrap-Up 1295

31 Web Services 1299
31.1 Introduction 1300
31.2 Web Service Basics 1302
31.3 Simple Object Access Protocol (SOAP) 1302
31.4 Representational State Transfer (REST) 1302
31.5 JavaScript Object Notation (JSON) 1303
31.6 Publishing and Consuming SOAP-Based Web Services 1303
31.6.1 Creating a Web Application Project and Adding a Web Service Class in NetBeans 1303
31.6.2 Defining the WelcomeSOAP Web Service in NetBeans 1304
31.6.3 Publishing the WelcomeSOAP Web Service from NetBeans 1307
31.6.4 Testing the WelcomeSOAP Web Service with GlassFish Application Server’s Tester Web Page 1308
31.6.5 Describing a Web Service with the Web Service Description Language (WSDL) 1309
31.6.6 Creating a Client to Consume the WelcomeSOAP Web Service 1310
31.6.7 Consuming the WelcomeSOAP Web Service 1312
31.7 Publishing and Consuming REST-Based XML Web Services 1315
31.7.1 Creating a REST-Based XML Web Service 1315
31.7.2 Consuming a REST-Based XML Web Service 1318
31.8 Publishing and Consuming REST-Based JSON Web Services 1320
31.8.1 Creating a REST-Based JSON Web Service 1320
31.8.2 Consuming a REST-Based JSON Web Service 1322
31.9 Session Tracking in a SOAP Web Service 1324
31.9.1 Creating a Blackjack Web Service 1325
31.9.2 Consuming the Blackjack Web Service 1328
31.10 Consuming a Database-Driven SOAP Web Service 1339
31.10.1 Creating the Reservation Database 1340
31.10.2 Creating a Web Application to Interact with the Reservation Service 1343
31.11 Equation Generator: Returning User-Defined Types 1346
31.11.1 Creating the EquationGeneratorXML Web Service 1349
31.11.2 Consuming the EquationGeneratorXML Web Service 1350
31.11.3 Creating the EquationGeneratorJSON Web Service 1354
31.11.4 Consuming the EquationGeneratorJSON Web Service 1354
31.12 Wrap-Up 1357

A Operator Precedence Chart 1365
B ASCII Character Set 1367
C Keywords and Reserved Words 1368
D Primitive Types 1369
E Using the Java API Documentation 1370
E.1 Introduction 1370
E.2 Navigating the Java API 1370
F Using the Debugger 1378
F.1 Introduction 1379
F.2 Breakpoints and the run, stop, cont and print Commands 1379
F.3 The print and set Commands 1383
F.4 Controlling Execution Using the step, step up and next Commands 1385
F.5 The watch Command 1388
F.6 The clear Command 1391
F.7 Wrap-Up 1393
G Formatted Output 1395
G.1 Introduction 1396
G.2 Streams 1396
G.3 Formatting Output with printf 1396
G.4 Printing Integers 1397
G.5 Printing Floating-Point Numbers 1398
G.6 Printing Strings and Characters 1400
G.7 Printing Dates and Times 1401
G.8 Other Conversion Characters 1403
G.9 Printing with Field Widths and Precisions 1405
G.10 Using Flags in the printf Format String 1407
G.11 Printing with Argument Indices 1411
G.12 Printing Literals and Escape Sequences 1411
G.13 Formatting Output with Class Formatter 1412
G.14 Wrap-Up 1413
H Number Systems 1418
H.1 Introduction 1419
H.2 Abbreviating Binary Numbers as Octal and Hexadecimal Numbers 1422
H.3 Converting Octal and Hexadecimal Numbers to Binary Numbers 1423
H.4 Converting from Binary, Octal or Hexadecimal to Decimal 1423
H.5 Converting from Decimal to Binary, Octal or Hexadecimal 1424
H.6 Negative Binary Numbers: Two’s Complement Notation 1426
I GroupLayout 1431
I.1 Introduction 1431
I.2 GroupLayout Basics 1431
I.3 Building a ColorChooser 1432
I.4 GroupLayout Web Resources 1442
J Java Desktop Integration Components 1443
J.1 Introduction 1443
J.2 Splash Screens 1443
J.3 Desktop Class 1445
J.4 Tray Icons 1447
K Mashups 1449
K.1 Introduction 1449
K.2 Popular Mashups 1449
K.3 APIs Commonly Used in Mashups 1450
K.4 Deitel Mashups Resource Center 1450
K.5 Deitel RSS Resource Center 1451
K.6 Mashup Performance and Reliability Issues 1451
L Unicode® 1452
L.1 Introduction 1452
L.2 Unicode Transformation Formats 1453
L.3 Characters and Glyphs 1454
L.4 Advantages/Disadvantages of Unicode 1454
L.5 Using Unicode 1455
L.6 Character Ranges 1457
Appendices on the Web 1459
Index 1461

Appendices M—Q are PDF documents posted online at the book’s Companion Website (www.pearsonhighered.com/deitel/).
M Creating Documentation with javadoc M-1
M.1 Introduction M-1
M.2 Documentation Comments M-1
M.3 Documenting Java Source Code M-1
M.4 javadoc M-8
M.5 Files Produced by javadoc M-9
N Bit Manipulation N-1
N.1 Introduction N-1
N.2 Bit Manipulation and the Bitwise Operators N-1
N.3 BitSet Class N-11
O Labeled break and continue Statements O-1
O.1 Introduction O-1
O.2 Labeled break Statement O-1
O.3 Labeled continue Statement O-2
P UML 2: Additional Diagram Types P-1
P.1 Introduction P-1
P.2 Additional Diagram Types P-1
Q Design Patterns Q-1
Q.1 Introduction Q-1
Q.2 Creational, Structural and Behavioral Design Patterns Q-2
Q.2.1 Creational Design Patterns Q-3
Q.2.2 Structural Design Patterns Q-5
Q.2.3 Behavioral Design Patterns Q-6
Q.2.4 Conclusion Q-7
Q.3 Design Patterns in Packages java.awt and javax.swing Q-7
Q.3.1 Creational Design Patterns Q-7
Q.3.2 Structural Design Patterns Q-8
Q.3.3 Behavioral Design Patterns Q-10
Q.3.4 Conclusion Q-13
Q.4 Concurrency Design Patterns Q-14
Q.5 Design Patterns Used in Packages java.io and java.net Q-15
Q.5.1 Creational Design Patterns Q-15
Q.5.2 Structural Design Patterns Q-15
Q.5.3 Architectural Patterns Q-16
Q.5.4 Conclusion Q-19
Q.6 Design Patterns Used in Package java.util Q-19
Q.6.1 Creational Design Patterns Q-19
Q.6.2 Behavioral Design Patterns Q-19
Q.7 Wrap-Up Q-20

About the AuthorsPaul J. Deitel,CEO and Chief Technical Officer of Deitel & Associates, Inc., is a graduate of MIT’s Sloan School of Management, where he studied Information Technology. He holds the Java Certified Programmer and Java Certified Developer certifications, and has been designated by Sun Microsystems as a Java Champion. Through Deitel & Associates, Inc., he has delivered Java, C, C++, C# and Visual Basic courses to industry clients, including IBM, Sun Microsystems, Dell, Lucent Technologies, Fidelity, NASA at the Kennedy Space Center, the National Severe Storm Laboratory, White Sands Missile Range, Rogue Wave Software, Boeing, Stratus, Cambridge Technology Partners, Open Environment Corporation, One Wave, Hyperion Software, Adra Systems, Entergy, CableData Systems, Nortel Networks, Puma, iRobot, Invensys and many more. He has also lectured on Java and C++ for the Boston Chapter of the Association for Computing Machinery. He and his father, Dr. Harvey M. Deitel, are the world’s best-selling programming language textbook authors.


The interdisciplinary nature of the SRCCL

Assessing the land system in view of the multiple challenges that are covered by the SRCCL requires a broad, inter-disciplinary perspective. Methods, core concepts and definitions are used differently in different sectors, geographic regions, and across academic communities addressing land systems, and these concepts and approaches to research are also undergoing a change in their interpretation through time. These differences reflect varying perspectives, in nuances or emphasis, on land as components of the climate and socio-economic systems. Because of its inter-disciplinary nature, the SRCCL can take advantage of these varying perspectives and the diverse methods that accompany them. That way, the report aims to support decision- makers across sectors and world regions in the interpretation of its main findings and support the implementation of solutions.