Parkinson Disease: US Eastern Zone

Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. · Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA. · Physiol Rev. · Pubmed #19126755 links to  free full text

Abstract: The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a "receptive substance," from which the idea of a "receptor" came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

McGuckin J, Parkinson K. · Vascular Access Centers, Philadelphia Vascular Institute, Philadelphia, PA, USA. · Tech Vasc Interv Radiol. · Pubmed #19100949 No free full text.

Abstract: Minimally-invasive medicine has continually progressed from its beginning in the 1960's. Evolution of technology and techniques have led to treatment of new disease states in minimally-invasive therapies. Now the venue of those therapies is shifting outpatient procedures from the hospital and into outpatient centers.

Pandya M, Kubu CS, Giroux ML. · Center for Neurological Restoration, Neurological Institute, Cleveland Clinic Foundation, OH 44195, USA. · Cleve Clin J Med. · Pubmed #19088004 links to  free full text

Abstract: Nonmotor symptoms are common in Parkinson disease and can significantly worsen the health and quality of life of the patient and family members. These symptoms can be broadly categorized as sensory, autonomic, cognitive-behavioral, and sleep-related. Clinicians can improve the care of these patients by recognizing and addressing these problems.

Sommer DB, Stacy MA. · Movement Disorders Center, Duke University Medical Center, DUMC Box 3333, Durham, NC 27710, USA. · Expert Rev Neurother. · Pubmed #19086879 No free full text.

Abstract: Parkinson's disease (PD) is a common, debilitating neurodegenerative disorder that creates a significant burden for patients, family members and society at large. Major unmet needs include effective therapies that could favorably modify the underlying pathogenetic processes in PD, and better control of motor and nonmotor symptoms in advanced-stage disease. This review examines the current state of development of potential PD therapies, including dopaminergic therapies, modulators of adenosine and glutamate receptors, cell-based therapies, genetic therapies and device-based therapies. In addition, research into potential neuroprotective agents and pipeline therapies for nonmotor symptoms of PD are summarized.

Robottom BJ, Mullins RJ, Shulman LM. · Department of Neurology, University of Maryland School of Medicine, 22 South Greene Street N4W46, Baltimore, MD 21201, USA. · Expert Rev Neurother. · Pubmed #19086876 No free full text.

Abstract: Pregnancy in Parkinson's disease (PD) is an uncommon occurrence. Available reports suggest that there may be a worsening of PD symptom severity related to pregnancy. In this special report, medical literature on pregnancy in PD will be reviewed with regard to disease progression and the safety of antiparkinsonian medications. A case report of pregnancy in a woman with PD will be described. It is speculated that the symptoms of PD may be affected by changing hormone levels.

Wider C, Wszolek ZK. · Department of Neurology, Cannaday Building 2E, Mayo Clinic, 4500 San Pablo Road, Jacksonville, Florida 32224, USA. · Lancet Neurol. · Pubmed #19081502 No free full text.

This publication has no abstract.

Henchcliffe C, Shungu DC, Mao X, Huang C, Nirenberg MJ, Jenkins BG, Beal MF. · Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10021, USA. · Ann N Y Acad Sci. · Pubmed #19076443 No free full text.

Abstract: Parkinson's disease (PD) is a common and often devastating neurodegenerative disease affecting up to one million individuals in the United States alone. Multiple lines of evidence support mitochondrial dysfunction as a primary or secondary event in PD pathogenesis; a better understanding, therefore, of how mitochondrial function is altered in vivo in brain tissue in PD is a critical step toward developing potential PD biomarkers. In vivo study of mitochondrial metabolism in human subjects has previously been technically challenging. However, proton and phosphorus magnetic resonance spectroscopy ((1)H and (31)P MRS) are powerful noninvasive techniques that allow evaluation in vivo of lactate, a marker of anaerobic glycolysis, and high energy phosphates, such as adenosine triphosphate and phosphocreatine, directly reflecting mitochondrial function. This article reviews previous (1)H and (31)P MRS studies in PD, which demonstrate metabolic abnormalities consistent with mitochondrial dysfunction, and then presents recent (1)H MRS data revealing abnormally elevated lactate levels in PD subjects.

Zhou C, Huang Y, Przedborski S. · Department of Neurology, Columbia University, New York, NY 10032, USA. · Ann N Y Acad Sci. · Pubmed #19076434 No free full text.

Abstract: Parkinson's disease (PD) is a common adult-onset neurodegenerative disorder. Typically PD is a sporadic neurological disorder, and over time affected patients see their disability growing and their quality of life declining. Oxidative stress has been hypothesized to be linked to both the initiation and the progression of PD. Preclinical findings from both in vitro and in vivo experimental models of PD suggest that the neurodegenerative process starts with otherwise healthy neurons being hit by some etiological factors, which sets into motion a cascade of deleterious events. In these models initial molecular alterations in degenerating dopaminergic neurons include increased formation of reactive oxygen species, presumably originating from both inside and outside the mitochondria. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, time-course experiments suggest that oxidative stress is an early event that may directly kill some of the dopaminergic neurons. In this model it seems that oxidative stress may play a greater role in the demise of dopaminergic neurons indirectly by activating intracellular, cell death-related, molecular pathways. As the neurodegenerative process evolves in the MPTP mouse model, indices of neuroinflammation develop, such as microglial activation. The latter increases the level of oxidative stress to which the neighboring compromised neurons are subjected to, thereby promoting their demise. However, these experimental studies have also shown that oxidative stress is not the sole deleterious factor implicated in the death of dopaminergic neurons. Should a similar multifactorial cascade underlie dopaminergic neuron degeneration in PD, then the optimal therapy for this disease may have to rely on a cocktail of agents, each targeting a different critical component of this hypothesized pathogenic cascade. If correct, this may be a reason why neuroprotective trials using a single agent, such as an antioxidant, have thus far generated disappointing results.

Mattson MP. · Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD 21224, USA. · Ann N Y Acad Sci. · Pubmed #19076369 links to  free full text

Abstract: Glutamate's role as a neurotransmitter at synapses has been known for 40 years, but glutamate has since been shown to regulate neurogenesis, neurite outgrowth, synaptogenesis, and neuron survival in the developing and adult mammalian nervous system. Cell-surface glutamate receptors are coupled to Ca(2+) influx and release from endoplasmic reticulum stores, which causes rapid (kinase- and protease-mediated) and delayed (transcription-dependent) responses that change the structure and function of neurons. Neurotrophic factors and glutamate interact to regulate developmental and adult neuroplasticity. For example, glutamate stimulates the production of brain-derived neurotrophic factor (BDNF), which, in turn, modifies neuronal glutamate sensitivity, Ca(2+) homeostasis, and plasticity. Neurotrophic factors may modify glutamate signaling directly, by changing the expression of glutamate receptor subunits and Ca(2+)-regulating proteins, and also indirectly by inducing the production of antioxidant enzymes, energy-regulating proteins, and antiapoptotic Bcl-2 family members. Excessive activation of glutamate receptors, under conditions of oxidative and metabolic stress, may contribute to neuronal dysfunction and degeneration in diseases ranging from stroke and Alzheimer's disease to psychiatric disorders. By enhancing neurotrophic factor signaling, environmental factors such as exercise and dietary energy restriction, and chemicals such as antidepressants may optimize glutamatergic signaling and protect against neurological disorders.

Richter JE. · Department of Medicine, Temple University School of Medicine, 3401, North Broad Street, 801 Parkinson Pavilion, Philadelphia, PA 19140, USA. · Expert Rev Gastroenterol Hepatol. · Pubmed #19072391 No free full text.

Abstract: Achalasia cannot be cured. Instead, our goal is to relieve symptoms of dysphagia and regurgitation, improve esophageal emptying and prevent the development of megaesophagus. The most definitive therapies are pneumatic dilation and surgical myotomy. The overall success of grade pneumatic dilation is 78%, with women and older patients performing best. Laparoscopic myotomy has an overall success rate of 85%, but can be complicated by the sequelae of severe acid reflux disease. Young patients, especially men, are the best candidates for surgical myotomy. There are no prospective, randomized studies comparing these two procedures. Botulinum toxin injections into the esophagus and smooth muscle relaxants are reserved for older patients or those with major comorbid illnesses. Some patients with end-stage achalasia will require esophagectomy.

Kazantsev AG, Kolchinsky AM. · Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Bldg 114, 3300 16th St, Charlestown, MA 02129-4404, USA. · Arch Neurol. · Pubmed #19064744 No free full text.

Abstract: Selective death of nigrostriatal neurons, which leads to Parkinson disease, is explained by misfolding of brain protein alpha-synuclein. Herein, we review the data supporting this concept, propose a scheme of events leading to synuclein-induced neuronal death, and discuss protein deacetylase sirtuins as new potential therapeutic targets involved in this process.

Lewitt PA. · Department of Neurology, Henry Ford Hospital, and the Department of Neurology, Wayne State University School of Medicine, Detroit, USA. · N Engl J Med. · Pubmed #19052127 No free full text.

This publication has no abstract.

Farooq MU, Naravetla B, Moore PW, Majid A, Gupta R, Kassab MY. · Department of Neurology and Ophthalmology, Michigan State University, East Lansing, MI, USA. · Clin Neuropharmacol. · Pubmed #19050413 No free full text.

Abstract: Sildenafil, a phosphodiesterase-5 inhibitor commonly used for erectile dysfunction, may also have a beneficial therapeutic effect in the treatment of stroke, subarachnoid hemorrhage, dementia, learning, and neurodegenerative disorders by enhancing angiogenesis and neurogenesis. It also favorably influences the nitric oxide-cyclic guanosine monophosphate pathways, which are involved in the pathogenesis of a number of neurological diseases. Its potential therapeutic role in the treatment of the neurological disorders mentioned above is still under preclinical investigation. Sildenafil is currently being used to treat erectile dysfunction in patients with multiple sclerosis, Parkinson disease, multisystem atrophy, and spinal cord injury by improving their neurologically related erectile dysfunction. Conversely, it has been implicated in a number of neurological problems, such as intracerebral hemorrhage, migraine, seizure, transient global amnesia, nonarteritic anterior ischemic optic neuropathy, macular degeneration, branch retinal artery occlusion, and ocular muscle palsies. Thus, preclinical and very limited clinical data suggest that sildenafil may have therapeutic potential in selected neurological disorders. However, numerous reports are available regarding neurological adverse events ascribed to the drug. Although sildenafil shows some promise as a therapeutic agent in selected neurological disorders, well-designed clinical trials are needed before the agent can be recommended for use in any neurological disorder.

Hadjiconstantinou M, Neff NH. · Division of Molecular Neuropsychopharmacology, Department of Psychiatry, College of Medicine, Ohio State University, Columbus, OH 43210, USA. · CNS Neurosci Ther. · Pubmed #19040557 No free full text.

Abstract: Aromatic L-amino acid decarboxylase (AAAD) is an essential enzyme for the formation of catecholamines, indolamines, and trace amines. Moreover, it is a required enzyme for converting L-DOPA to dopamine when treating patients with Parkinson's disease (PD). There is now substantial evidence that the activity of AAAD in striatum is regulated by activation and induction, and second messengers play a role. Enzyme activity can be modulated by drugs acting on a number of neurotransmitter receptors including dopamine (D1-4), glutamate (NMDA), serotonin (5-HT(1A), 5-HT(2A)) and nicotinic acetylcholine receptors. Generally, antagonists enhance AAAD activity; while, agonists may diminish it. Enhancement of AAAD activity is functional, as the formation of dopamine from exogenous L-DOPA mirrors activity. Following a lesion of nigrostriatal dopaminergic neurons, AAAD in striatum responds more robustly to pharmacological manipulations, and this is true for the decarboxylation of exogenous L-DOPA as well. We review the evidence for parallel modulation of AAAD activity and L-DOPA decarboxylation and propose that this knowledge can be exploited to optimize the formation of dopamine from exogenous L-DOPA. This information can be used as a blue print for the design of novel L-DOPA treatment adjuvants to benefit patients with PD.

Abbas A, Roth BL. · Case Western Reserve University School of Medicine, Biochemistry, Cleveland, OH 44106, USA. · Expert Opin Pharmacother. · Pubmed #19040345 No free full text.

Abstract: BACKGROUND: Pimavanserin tartrate is the first 5-HT(2A) inverse agonist to enter clinical trials as a treatment for L-dopa-induced psychosis in Parkinson's disease and for augmentation of low-dose risperidone treatment in schizophrenia. Pimavanserin is also being evaluated as a possible anti-insomnia drug. OBJECTIVE: To discuss the potential of pimavanserin to fill multiple therapeutic needs. METHODS: The problems with currently approved antipsychotics and sleep agents are explored to highlight how pimavanserin might address some longstanding issues in the treatment of psychosis and insomnia. RESULTS/CONCLUSIONS: In Phase II clinical trials, pimavanserin seemed to be safe, well-tolerated and efficacious in treating L-dopa-induced psychosis without worsening motor symptoms. Pimavanserin also potentiated the therapeutic effects of low-dose risperidone, reduced haloperidol-induced akathisia, and increased slow-wave sleep in older individuals.

Gandhi PN, Chen SG, Wilson-Delfosse AL. · Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44106-4965, USA. · J Neurosci Res. · Pubmed #19025767 No free full text.

Abstract: Parkinson's disease (PD) is the most common neurodegenerative movement disorder, with a prevalence of more than 1% after the age of 65 years. Mutations in the gene encoding leucine-rich repeat kinase-2 (LRRK2) have recently been linked to autosomal dominant, late-onset PD that is clinically indistinguishable from typical, idiopathic disease. LRRK2 is a multidomain protein containing several protein interaction motifs as well as dual enzymatic domains of GTPase and protein kinase activities. Disease-associated mutations are found throughout the multidomain structure of the protein. LRRK2, however, is unique among the PD-causing genes, because a missense mutation, G2019S, is a frequent determinant of not only familial but also sporadic PD. Thus, LRRK2 has emerged as a promising therapeutic target for combating PD. In this Mini-Review, we look at the current state of knowledge regarding the domain structure, amino acid substitutions, and potential functional roles of LRRK2.

Bras J, Singleton A, Cookson MR, Hardy J. · Molecular Genetics Unit, National Institutes on Aging, Bethesda, MD, USA. · FEBS J. · Pubmed #19021754 No free full text.

Abstract: Heterozygous loss-of-function mutations at the glucosecerebrosidase locus have recently been shown to be a potent risk factor for Lewy body disease. Based on this observation, we have re-evaluated the likelihood that the different PARK loci (defined using clinical criteria for disease) may be misleading attempts to find common pathways to pathogenesis. Rather, we suggest, grouping the different loci which lead to different Lewy body disease may be more revealing. Doing this, we suggest that several of the genes involved in disparate Lewy body diseases impinge on ceramide metabolism and we suggest that this may be a common theme for pathogenesis.

Germain D. · Mount Sinai School of Medicine, Division of Hematology/Oncology Box 1079, One Gustave L. Levy Place, New York, NY 11029, USA. · Mol Microbiol. · Pubmed #19019155 No free full text.

Abstract: The ubiquitin-independent protein quality control of matrix proteins of the mitochondrion is well characterized and until recently the mitochondrion was considered a 'ubiquitination-free' organelle. However, a number of studies now indicate multiple roles of the ubiquitin-proteasome pathway in the regulation and maintenance of mitochondrial integrity. Of particular interest to this review is the finding of a mitochondrial ubiquitin-dependent protein quality control and that this pathway may share similarity to the endoplasmic reticulum-associated degradation (ERAD) pathway that acts to eliminate misfolded proteins from the lumen of the endoplasmic reticulum. The potential cross-talk between the ubiquitin-dependent and -independent protein quality controls and their implications in ageing and neurodegenerative diseases, notably in Parkinson's disease, are discussed.

Henchcliffe C, Beal MF. · Department of Neurology and Neuroscience at the Weill Medical College of Cornell University, New York, NY 10021, USA. · Nat Clin Pract Neurol. · Pubmed #18978800 No free full text.

Abstract: Parkinson disease (PD) is associated with progressive loss of dopaminergic neurons in the substantia nigra, as well as with more-widespread neuronal changes that cause complex and variable motor and nonmotor symptoms. Recent rapid advances in PD genetics have revealed a prominent role for mitochondrial dysfunction in the pathogenesis of the disease, and the products of several PD-associated genes, including SNCA, Parkin, PINK1, DJ-1, LRRK2 and HTR2A, show a degree of localization to the mitochondria under certain conditions. Impaired mitochondrial function is likely to increase oxidative stress and might render cells more vulnerable to this and other related processes, including excitotoxicity. The mitochondria, therefore, represent a highly promising target for the development of disease biomarkers by use of genetic, biochemical and bioimaging approaches. Novel therapeutic interventions that modify mitochondrial function are currently under development, and a large phase III clinical trial is underway to examine whether high-dose oral coenzyme Q10 will slow disease progression. In this Review, we examine evidence for the roles of mitochondrial dysfunction and increased oxidative stress in the neuronal loss that leads to PD and discuss how this knowledge might further improve patient management and aid in the development of 'mitochondrial therapy' for PD.

González-Fernández M, Daniels SK. · Department of Physical Medicine and Rehabilitation, Johns Hopkins University, School of Medicine, 600 North Wolfe Street, Phipps 174, Baltimore, MD 21287, USA. · Phys Med Rehabil Clin N Am. · Pubmed #18940646 No free full text.

Abstract: Dysphagia is a common problem in neurologic disease. The authors describe rates of dysphagia in selected neurologic diseases, and the evaluation and treatment of dysphagia in this population. Applicable physiology and aspects of neural control are reviewed. The decision-making process to determine oral feeding versus alternative means of alimentation is examined.

Elmer LW, Bertoni JM. · Center for Neurological Disorders, Parkinson's Disease and Movement Disorders Program University of Toledo College of Medicine, Department of Neurology, 3120 Glendale Avenue, Toledo, OH 43614, USA. · Expert Opin Pharmacother. · Pubmed #18937611 No free full text.

Abstract: BACKGROUND: The role of monoamine oxidase type B inhibitors in the treatment of Parkinson's disease has expanded with the new monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets. As primary therapy in early disease monoamine oxidase B inhibitors reduce motor disability and delay the need for levodopa. In more advanced disease requiring levodopa, adjunctive monoamine oxidase B inhibitors reduce 'off' time and may improve gait and freezing. OBJECTIVE: Rasagiline and selegiline oral disintegrating tablets may reduce the safety risks associated with the amfetamine and methamfetamine metabolites of conventional oral selegiline while retaining or improving therapeutic efficacy. METHODS: Articles were identified by searches of PubMed and searches on the Internet and reviewed. All articles and other referenced materials were retrieved using the keywords 'Parkinson's disease', 'treatment' and 'monoamine oxidase B inhibitor' and were published between 1960 and 2007, with older references selected for historical significance. Only papers published in English were reviewed. CONCLUSION: Accumulating data support the use of monoamine oxidase B inhibitors as monotherapy for early and mild Parkinson's disease and as adjunctive therapy for more advanced Parkinson's disease with levodopa-associated motor fluctuations. The recently released monoamine oxidase B inhibitor rasagiline and a new formulation, selegiline oral disintegrating tablets, have potential advantages over conventional oral selegiline.

Hess JJ, Malilay JN, Parkinson AJ. · National Center for Environmental Health, CDC, Atlanta, Georgia 30341-3717, USA. · Am J Prev Med. · Pubmed #18929973 No free full text.

Abstract: Climate change-related risks are place-specific and path-dependent. Accordingly, location is an important determinant of hazardous exposure, and certain places will bear more risk than others. This article reviews the major environmental exposures associated with risky places in the U.S., including coastal regions, islands, the desert Southwest, vectorborne and zoonotic disease border regions, cities, and the U.S. Arctic (Alaska), with emphasis on exposures and vulnerable populations of concern. In addition to these hotspots, this study considers the ways in which the concept of place--the sense of human relationship with particular environments--will play a key role in motivating, developing, and deploying an effective public health response. In considering the importance of place, we highlight the concepts of community resilience and risk management, key aspects of a robust response to climate change in public health and other sectors.

Maguire-Zeiss KA. · Department of Neuroscience, Georgetown University Medical Center, 3970 Reservoir Road, Washington, DC 20057, United States. · Pharmacol Res. · Pubmed #18840530 No free full text.

Abstract: Parkinson's disease is a progressive age-related neurodegenerative disease with invariant loss of substantia nigra dopamine neurons and striatal projections. This disorder is well known for the associated motoric symptoms including resting tremor and the inability to initiate movement. However, it is now apparent that Parkinson's disease is a multisystem disorder with patients exhibiting symptoms derived from peripheral nervous system and extra-nigral dysfunctions in addition to the prototypical nigrostriatal damage. Although the etiology for sporadic Parkinson's disease is unknown, information gleaned from both familial forms of the disease and animal models places misfolded alpha-synuclein at the forefront. The disease is currently without a cure and most therapies target the motoric symptoms relying on increasing dopamine tone. In this review, the role of alpha-synuclein in disease pathogenesis and as a potential therapeutic target focusing on toxic conformers of this protein is considered. The addition of protofibrillar/oligomer-directed neurotherapeutics to the existing armamentarium may extend the symptom-free stage of Parkinson's disease as well as alleviate pathogenesis.

Kieburtz K. · University of Rochester Medical Center, 1351 Mt. Hope Ave., Ste. 223, Rochester, NY 14620, USA. · J Neurol. · Pubmed #18821085 No free full text.

Abstract: Dopaminergic treatment of Parkinson's disease (PD) leads to significant improvement in Parkinsonian features; however, the treatment response is hampered by the appearance of motor complications, including dyskinesias and motor fluctuations. These motor complications have a significant negative impact on quality-of-life. Therapeutic strategies using different types and timing of dopaminergic therapy may influence the emergence of motor complications. While sustained release preparations of levodopa have not shown benefit over immediate release preparations, the early combination of a dopamine agonist with levodopa appears to reduce the onset of motor fluctuations. An even larger body of evidence has found that initiating treatment with a dopamine receptor agonist (as compared to immediate release levodopa) is associated with a reduction in motor fluctuations, particularly dyskinesias. These data have led to evidence-based medicine evaluations indicating that the use of dopamine agonists is efficacious and clinically useful for the prevention of motor complications.

Edwards TM, Myers JP. · Department of Zoology, University of Florida, Gainesville, FL 32611, USA. · Cien Saude Colet. · Pubmed #18813540 links to  free full text

Abstract: Health or disease is shaped for all individuals by interactions between their genes and environment. Exactly how the environment changes gene expression and how this can lead to disease are being explored in a fruitful new approach to environmental health research, representative studies of which are reviewed here. We searched Web of Science and references of relevant publications to understand the diversity of gene regulatory mechanisms affected by environmental exposures with disease implications. Pharmaceuticals, pesticides, air pollutants, industrial chemicals, heavy metals, hormones, nutrition, and behavior can change gene expression through a broad array of gene regulatory mechanisms. Furthermore, chemically induced changes in gene regulation are associated with serious and complex human diseases, including cancer, diabetes and obesity, infertility, respiratory diseases, allergies, and neurodegenerative disorders such as Parkinson and Alzheimer diseases. The reviewed studies indicate that genetic predisposition for disease is best predicted in the context of environmental exposures. And the genetic mechanisms investigated in these studies offer new avenues for risk assessment research. Finally, we are likely to witness dramatic improvements in human health, and reductions in medical costs, if environmental pollution is decreased.