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1. Introduction
Diabetic neuropathy is a common microvascular complication of diabetes mellitus. Diabetic neuropathy is a major risk factor for non-traumatic amputations and is thought to play a role in the pathogenesis of other late complications of diabetes. The two major forms of diabetic neuropathy include generalized neuropathy and autonomic neuropathy. Genreralized neuropathy, affecting motor and sensory peripheral nerves can be subdivided further into polyneuropathies which affect multiple nerves and focal neuropathies. The most common form of generalized neuropathy is distal symmetrical polyneuropathy. Autonomic neuropathy affects peripheral autonomic nerves. These autonomic nerves innervate most organ systems of the body and the skin. Both distal symmetric polyneuropathy and autonomic neuropathy cause substantial morbidity and are associated with a high risk of mortality. The hypothesized mechanisms of diabetic neuropathy include ischemic effects caused by vascular abnormalities, disruption of neuronal metabolism, axonal transport mechanisms and repair capabilities, glycation of peripheral nervous system connective tissue, and glycation of Schwann cells or extracellular matrix. In this chapter, we discuss the diagnostic criteria, pathophysiology, epidemiology, and treatment of peripheral and autonomic neuropathy in type 1 diabetes.
2. Classification
Table 1 gives a detailed classification of the neuropathies observed in diabetes.
\n\t\t
\n\t\t
\n\t\t
\n\t\t
\n\t\t\t
Generalized Neuropathy
\n\t\t\t
Focal Neuropathies
\n\t\t\t
Autonomic Neuropathies
\n\t\t
\n\t\t
\n\t\t\t
Typical: Distal symmetric polyneuropathy (DSP)
\n\t\t\t
Compression:
\n\t\t\t
Cardiovascular autonomic neuropathy
\n\t\t
\n\t\t
\n\t\t\t
Atypical Neuropathy:
\n\t\t\t
Median -carpal tunnel
\n\t\t\t
Gastrointestinal autonomic neuropathy
\n\t\t
\n\t\t
\n\t\t\t
Insulin Neuritis/Treatment Neuropathy
\n\t\t\t
Ulnar -cubital tunnel
\n\t\t\t
Genitourinary autonomic neuropathy
\n\t\t
\n\t\t
\n\t\t\t
Inflammatory Neuropathy
\n\t\t\t
Fibular -fibular head
\n\t\t\t
Hypoglycemia unawareness and associated autonomic failure
3. Diabetic distal symmetric polyneuropathy in type 1 diabetes mellitus
3.1. Overview
Distal Symmetric Polyneuropathy (DSP) is the most common type of neuropathy affecting patients with type 1 diabetes. Polyneuropathy is the greatest risk factor for non-traumatic amputations and confers a higher mortality risk [3, 4]. The incidence of DSP increases with duration of diabetes and with degree of hyperglycemia [5]. In type 1 diabetes, typically the incidence of DSP is linked to other microvascular complications of nephropathy and retinopathy [6]. Unlike type 2 diabetes, polyneuropathy is rarely if ever present in the first five years of diagnosis. Metabolic memory in which improved metabolic control, even for a finite period, confers improved outcomes in the future is a phenomenon which was discovered with the Diabetes Complications and Control Treatment Trial, and may be an important factor to consider in the treatment of type 1 diabetic patients [7].
3.2. Diagnostic criteria
The case definition of typical DSP or diabetic sensorimotor polyneuropathy from the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Association of Physical Medicine and Rehabilitation is, “a combination of neuropathic symptoms, multiple signs, and abnormal electrodiagnostic studies” [8]. However, this does not distinguish typical DSP from atypical diabetic neuropathies [1]. A more precise definition for typical DSP proposed by neuromuscular experts at the 2011 Neurodiab Meeting suggested a tiered approach of possible, probable, confirmed and subclinical DSP. Possible DSP includes symptoms or signs of DSP such as decreased distal sensation or depressed ankle reflexes. Probable clinical DSP includes a combination of symptoms and signs of DSP. Confirmed DSP includes symptoms, signs, and abnormal nerve conduction study consistent with DSP (i.e. symmetric). Subclinical DSP would include patients with abnormal nerve conduction studies but no signs or symptoms of neuropathy [1]. Debate is ongoing as to whether abnormal skin biopsy with decreased epidermal nerve fiber density should be considered with nerve conduction study as a confirmatory test.
3.3. Epidemiology
The prevalence of DSP in type 1 diabetes mellitus has been postulated to be over 50% by 25 years of diagnosis [9, 10]. These data depend on measures used for quantification. Nerve conduction studies are typically more sensitive than monofilament tests and often show decreased conduction velocity in sensory and motor nerves prior to the development of signs or symptoms of sensory loss with monofilament and vibration testing [11]. More tests used, and more sensitive measures will increase prevalence statistics.
Risk factors for DSP incidence and severity in addition to duration of diabetes and age are hyperglycemia, systolic blood pressure, smoking, cholesterol, and height. The Diabetes Control and Complications Trial confirmed hyperglycemia as a significant risk factor for DSP in type 1 diabetes
*The DCCT was a groundbreaking study of patients with type 1 diabetes in the United States; a large, multicenter study designed to test whether improved glycemic control delayed the onset or progression of diabetic complications. The follow up epidemiologic study, EDIC (Epidemiology of Diabetes Interventions and Complications) continued to follow the same patients enrolled in DCCT, which is still ongoing.
. Interestingly, hyperglycemia alone has not been proven in prospective cohort studies of type 2 diabetes to delay progression in this population [12] which raises the question of whether hyperglycemia is the sole cause of DSP in type 2 diabetes.
Typical progression of DSP in type 1 is very slow, with incremental sensory loss over years and decades. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study data show minimal changes in conduction velocity and amplitudes over 5 year periods, which can reassure patients [13, 14]. Progression typically affects both large, myelinated fibers conveying tactile sensitivity, vibration and joint position sense, and small, unmyelinated fibers conveying temperature and pain sensation. Motor involvement is typically subclinical until later in the disease course. While slowed conduction velocities, particularly in the fibular nerve, are common early signs of DSP, weakness typically occurs later, first affecting the toes and then more proximal muscles.
Inflammatory neuropathies such as mononeuritis multiplex and diabetic amyotrophy affecting the plexus are less common in type 1 diabetes than type 2 [15]. Chronic inflammatory demyelinating polyneuropathy is also more common in type 2, but has not been shown to affect diabetic patients at an increased rate than the general population [16]. Acute painful neuropathy associated with weight loss and abrupt improvement in glycemic control occurs in both type 1 and type 2 patients. This type of neuropathy, formerly known as “insulin neuritis” typically has significant resolution within a year of onset [17].
Sensory symptoms include numbness, or alteration of sensation often described by patients as “wearing multiple socks” or “walking on wood”. Neuropathic pain when present can vary between sharp shooting pains, stabbing, or dull and aching. Muscle cramps in feet and legs are common complaints. Hand symptoms can occur when DSP progresses to include the hands in a length dependent process, but more commonly occur because of coexisting compression neuropathies in the hands [18, 19].
Coexisting polyneuropathy from other causes also occurs in type 1 diabetes patients and can account for as many as 10% of DSP cases [9]. The most common include alcoholic neuropathy, B12 deficiency and monoclonal gammopathies. Atypical presentations such as severe distal or proximal weakness, spasticity, faster progression over weeks to months should be signals that a coexistent polyneuropathy may be present and needs evaluation.
3.4. Pathophysiology
The polyol pathway was put forth as a possible cause of diabetic neuropathy over 30 years ago when aldose reductase inhibitors were first studied [20]. Since then, the pathophysiology of DSP in type 1 diabetes is still not completely known but several major pathways have been the focus of most studies. 1) increased flux through the polyol pathway; 2) advanced glycation end-products affecting proteins and lipids [21, 22]; 3) increased oxidative stress with impaired mitochondrial function [23, 24], 4) protein kinase C inhibition [25, 26] and 5) loss of nerve growth factors [27, 28]. Additional mechanisms that have been raised include inflammation, loss of nitric oxide, and hypoxia from microvascular damage [29]. Additional metabolic factors such as hypertriglyceridemia may be more pertinent to type 2 diabetes, although this also occurs in type 1 patients [30, 31]. Loss of ATP and AMP production through mitochondrial dysfunction may be a “final common pathway” for these mechanisms to cause neuronal injury [32].
The role of Schwann cells in DSP is still not completely understood. Schwann cells, not neurons produce aldose reductase [33] and are also the source of nerve growth factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor [34, 35]. Schwann cells in culture tend to be more resistant to hyperglycemia than neurons. However, the most recent evidence suggests unmyelinated fibers to be more sensitive to hyperglycemia than myelinated fibers [36]. These may have important implications for biomarkers in treatment studies.
3.5. Assessment
The assessment of DSP in type 1 diabetes significantly affects the sensitivity and specificity cited. The simplest assessments used are loss of ankle deep tendon reflexes and detection of pressure from a 10g monofilament. Monofilament sensitivity alone ranges from 20% to 64% [37, 38] and likely improves if multiple sites on the foot are tested (8 sites recommended). Nerve conduction studies measuring sensory and motor nerve action potential amplitude, latency, and conduction velocity are typically used for most studies [14]. The most common nerves assessed are sural sensory and fibular motor nerves. These were shown by Dyck et al to be involved earliest [39]. The earliest finding is conduction velocity slowing in the fibular and sural nerves.
Additional measures used include quantitative sensory testing, which can be performed with multiple devices to measure vibration and thermal thresholds [40, 41]. This can be more sensitive than nerve conduction studies but is subjective and not well suited for diagnostic purposes [42]. Quantitative sensory testing is highly reproducible and has been used in several clinical neuropathy studies [43, 44]. Sural nerve biopsy is rarely performed for diagnosis due to its invasiveness (and cannot be repeated) and is usually used to evaluate for other forms of neuropathy such as chronic inflammatory demyelinating polyneuropathy, vasculitis, or inherited neuropathies. Skin biopsy with measurement of intraepidermal nerve fiber density has become more common, especially when combined with chemical axotomy with capsaicin to measure nerve regeneration [36]. Newer noninvasive methods used include confocal microscopy of corneal C fibers [45] or of Meissner corpuscles (mechanoreceptors) in the finger [46, 47].
3.6. Management
Management of DSP is largely supportive. The main therapeutic aim is to achieve normoglycemia or HgA1c less than 7 [13]. This can be accomplished with frequent self-monitoring and using insulin pumps for continuous subcutaneous insulin infusion or multiple daily injections. Both the EURODIAB and the Diabetes Control and Complications Trial confirmed therapeutic efficacy in delaying progression of DSP with lower glycemic levels [5, 13]. For treatment of insulin neuritis, management is largely supportive and usually requires relaxing hyperglycemia control somewhat. Inflammatory neuropathies may respond to pulsed IV steroids and intravenous immunoglobulins but class A evidence is still lacking [48, 49]. Diabetic chronic inflammatory demyelinating polyneuropathy is managed similarly to idiopathic chronic inflammatory demyelinating polyneuropathy [50].
Foot care is critical once DSP occurs. Patients should be instructed to inspect their feet every night for new ulcerations, blisters or cuts. Wearing shoes at all times will also decrease the chance of potential injury. Feeling bathwater with hands or more proximal leg is also helpful to avoid burns from insensate feet. As neuropathy occurs, the foot structure will change due to muscle atrophy and due to fractures from insensate feet (Charcot foot). Orthotic inserts may be helpful in preventing further ulceration and stabilizing the feet [51].
Falls are an important complication in DSP and need to be screened for at clinic visits. Evaluation by a physical therapist can be helpful in identifying whether a cane, four-point canes, walkers, wheelchairs should be singular. Home evaluations to improve lighting, minimize obstructions and irregular floors like loose rugs are also important. Adding grab bars in bath areas and minimizing steps can be helpful changes to homes.
3.7. Treatment of neuropathic pain
A significant number of patients with DSP (16-60%) have symptoms of neuropathic pain [52, 53]. One UK study suggested that painful symptoms were more prevalent in type 2 than type 1 diabetes [53]. Typical pain symptoms are delayed compared to signs of neuropathy in type 1 diabetes [54, 55]. The etiology of neuropathic pain in DSP has been thought to be due to abnormalities in C-fiber nerve endings causing aberrant signaling through protein kinase C [26], increased transient receptor potential vanilloid 1 expression [56], dysregulation of ion channels [57], abnormal nerve growth factor levels [58] and possibly dysregulation of descending pain pathways [59].
Typical pain symptoms described include “burning”, “stabbing”, “needle-like”, “shooting”, “electric” etc. Patients often complain of allodynia, e.g. normal sensations become painful such as the touch of bedcovers to the feet, as well as hyperalgesia (painful sensations such as pinprick are unbearably painful). Pain is typically worse at night, and with activities such as walking and standing. Mononeuropathies such as carpal tunnel syndrome can also cause nocturnal paresthesias. Pain symptoms are typically not completely relieved with medications. Pain can be moderate to severe with an average of 5.8/10 on a pain scale [60].
Medications used for neuropathic pain include traditional pain medications such as opioids and tramadol, antiepileptic agents and antidepressants (Table 2) [61]. Typically patients require large doses of opiates for pain relief, and long acting opiates are preferred to provide sustained relief. Sedation, constipation, pharmacologic tolerance and addiction issues are significant barriers and usually prohibit opiates as first line pain treatment in neuropathic pain. Mexiletine, a sodium channel blocker and anti-arrhythmic agent has also been shown to have some analgesic effects [62].
Alpha2-delta inhibitors gabapentin and pregabalin are the most commonly used anti-epileptic medications. These medications act at the dorsal horn of the spinal cord to inhibit voltage gated calcium channels [63, 64]. The advantage of gabapentin and pregabalin is their renal excretion and lack of interaction with other medications. Main side effects include drowsiness, dizziness, peripheral edema, weight gain, and myoclonic jerks at higher doses. Gabapentin is typically initiated at 300 mg up to three times a day and can be escalated up to 4800 mg in divided doses. Its short half-life requires three to four times a day dosing for optimal pain relief. Pregabalin has a longer half-life and is typically dosed twice a day although some patients benefit from dosing three times a day. Pregabalin is usually started at 75 mg twice a day and titrated up to 300 mg twice a day. Consultation with a nephrologist in dialysis dependent patients is needed due to renal excretion, but does not preclude use in these patients. Typically nephrologists will administer one dose after dialysis. Other anticonvulsants used for neuropathic pain include carbamazepine, oxcarbazepine, valproic acid, lamotrigine, lacosamide, and phenytoin.
Antidepressants acting on norepinephrine such as tricyclic antidepressants and the selective serotonin and norepinephrine reuptake inhibitor duloxetine are also helpful in treating neuropathic pain [65, 66]. Duloxetine is well tolerated, with few side effects. Caution should be used in patients with renal insufficiency as elevations of systolic blood pressure have been observed. Nausea can occur initially, but can be avoided with initiation at lower doses such as 20 -30 mg and slow titration up to 60 mg. Effectiveness of 120 mg was not statistically different from 60 mg in clinical studies, although some patients report improved benefit at higher doses [65]. Tricyclic antidepressants also have a benefit in patients reporting difficulty initiating sleep due to pain due to their sedating effects. Dosages of 25-100 mg amitriptyline 2 hours before bedtime are typically used. At higher doses and in elderly patients, an ECG should be obtained because of possible effects of tricyclics on QT prolongation and heart block. Side effects include drowsiness, urinary hesitancy, constipation, orthostatic hypotension and erectile dysfunction.
Topical creams are not typically efficacious for painful DSP. Capsaicin cream/patch has shown efficacy [67], but is typically not well tolerated due to the significant initial pain with application. Gloves need to be worn and avoidance of the eyes is necessary. Occasionally 1% lidocaine patches can be helpful in patients with focal mononeuropathies such as meralgia paresthetica (compression of the lateral femoral cutaneous nerve). Topical compounded creams containing gabapentin, amitriptyline, and ketamine have been used but there are no published reports on efficacy in placebo controlled studies.
*FDA approved indication for diabetic neuropathic pain.
4. Focal neuropathies
4.1. Overview and epidemiology
Other types of neuropathy which can occur include mononeuropathies, typically at compression points such as median mononeuropathy at the wrist, e.g. carpal tunnel syndrome, ulnar neuropathy at the elbow, and peroneal neuropathy at the knee. In the Rochester Diabetes Trial, these occurred at about the same frequency or higher in type 1 vs. type 2 patients [9]. Cranial neuropathies and truncal radiculopathy occur at an increased rate in diabetic patients, but prevalence data for type 1 and type 2 patients is not available. Pain is a common presenting symptom in ischemic ocular motor palsies and thoracic radiculopathies in diabetes [68, 69]. The Veterans Affairs study of type II patients showed decreased prevalence of cranial mononeuropathies with stricter glucose control but data is lacking for type 1 patients [70]. It is not uncommon for mononeuropathies to occur prior to the development of DSP or identification of diabetes, particularly in type 2 patients [71, 72]. This has not been described in type 1 patients.
Median mononeuropathy at the wrist, e.g. carpal tunnel syndrome is the most common mononeuropathy in diabetes and occurs three to four times as commonly in diabetics compared to healthy controls, and is more common in diabetics with DSP than without [72-74]. Median mononeuropathy has been reported as early as 11 years old [75]. Risk factors for development of carpal tunnel syndrome include obesity and lipid-lowering medications [74].
4.2. Pathophysiology
The pathophysiology of mononeuropathies in diabetes is not well understood. They are generally divided into compression-site mononeuropathies, occurring at typical compression points such as the transverse ligament in the wrist (median), cubital tunnel (ulnar nerve), across the knee (fibular nerve), the inguinal ligament (lateral femoral cutaneous nerve/meralgia paresthetica) and tarsal tunnel (tibial nerve). Cranial nerve mononeuropathies and thoracic radiculopathies, diabetic amyotrophies are thought to have an ischemic etiology, either due to microvascular disease (such as cranial nerve involvement) or inflammation (diabetic amyotrophy). Some patients (described in type 2 diabetes) have a rapid development of multiple mononeuropathies which is indistinguishable from a vasculitic mononeuritis multiplex in presentation and can be associated with inflammation on biopsy [76].
The greater prevalence of compression mononeuropathies in diabetes (20-30% of Type 1 and 2 patients) [9, 77] has been observed for decades, but the pathophysiology is not well known. Experimental compression neuropathies trigger Schwann cell proliferation, apoptosis causing local demyelination then remyelination. This occurs prior to the development of axonal degeneration [78]. The median nerve when visualized with ultrasonography is larger in patients with compression compared to healthy controls which may be due to remyelination [79]. It has been presumed that hyperglycemia injured nerves are more vulnerable to compression than normal nerves. Another possibility is lack of symptoms in the diabetic may make compression mononeuropathies worse because of delayed recognition [77]. Other possible etiologies include greater edema within the nerve and diabetic cheiroarthropathy (thickening/fibrosis of the flexor synovium from excessive connective tissue) [80, 81].
4.3. Assessment
Identification of mononeuropathies may be based on signs and symptoms localizable to a specific nerve in a diabetic patient (e.g. ptosis, diploplia in a Cranial nerve III/oculomotor nerve palsy). This is typically the case for cranial nerve palsies, optic neuropathies, thoracic radiculopathies, or lateral femoral cutaneous nerve palsy where the distribution of deficit is pathognemonic. If the symptoms and signs are specific to one cranial nerve in a previously diagnosed diabetic patient, imaging with magnetic resonance imaging, CT or other modality is typically not needed to confirm the diagnosis. Especially in cranial nerve III palsies, there is controversy whether imaging should occur in a diabetic patient with a classical papillary-sparing presentation [82, 83].
Mononeuropathies may be identified on testing with nerve conduction studies. This is more common in carpal tunnel syndrome, ulnar mononeuropathy, and fibular mononeuropathy which are often asymptomatic. Nerve conduction studies in compression mononeuropathies distally typically demonstrate slowing of conduction velocity across the compressed segment (ulnar, fibular, tibial nerve) or increased distal latency compared to nearby nerves (median nerve). Multiple nerves are often compared, or side to side comparisons are made to exclude underlying DSP.
For carpal tunnel syndrome, nerve ultrasound has become a more common procedure, demonstrating enlarged median nerve cross sectional area in the wrist in affected individuals compared to controls [84]. Thus far, no differentiation between ultrasound appearance of diabetic vs. non-diabetic nerves have been found [85]. Another study suggested a larger cross-sectional area of the tibial nerve at the tarsal tunnel in diabetic patients [86]. Further studies are still needed on the utility of this measure for diabetic patients. Magnetic resonance imaging is also used for assessment of carpal tunnel syndrome, but data in diabetes vs. control patients is lacking and cost is significantly higher than nerve conduction studies or ultrasound [87].
4.4. Treatment
Treatment of compression induced mononeuropathies is aimed at relieving the site of trauma. Bracing, avoiding extenuating activity, and changing postures are initial non-surgical approaches. Data for surgical approach to compressive neuropathy is better known in median mononeuropathies at the wrist (carpal tunnel syndrome) because of larger reported cohort studies. However, data are conflicting in regards to outcome of carpal tunnel syndrome surgical release with some studies showing poorer outcomes and some not significantly different from non-diabetic patients [88, 89]. This may occur due to differences in patient selection. Results of surgical release of the ulnar nerve at the cubital tunnel, the second most common mononeuropathy (2.1%) are worse compared to carpal tunnel syndrome [81, 90]. It is not clear whether this is due to underlying diabetic polyneuropathy or due to patient selection bias (misdiagnosis).
Treatment of ischemic induced mononeuropathies is typically supportive. Pain management is often needed for thoracic radiculopathies, meralgia paresthetica (lateral femoral cutaneous nerve palsy). Prisms or patching can be used for diploplia in ocular motor cranial nerve palsies (cranial nerve 3, 4, and 6). Taping of the eyelid and lubrication may be needed in facial nerve palsies to prevent corneal abrasion. Little data are available for prognosis. Many patients improve over 3-6 months, but some may have permanent muscle weakness or ptosis [91, 92]. Treatment with intravenous alpha-lipoic acid has also been reported as improving outcomes but was not placebo controlled [93]. Otherwise, treatment for mononeuropathies in diabetes is not significantly different than in non-diabetics.
5. Diabetic autonomic neuropathy
5.1. Overview
Autonomic neuropathy is a form of peripheral neuropathy affecting the nerves of the autonomic nervous system. Autonomic neuropathy most commonly affects organs of the cardiovascular, gastrointestinal, urinary, and reproductive systems, although any system of the body may be affected. Its etiology is poorly understood, but as with other forms of peripheral neuropathy long exposure to hyperglycemia, advanced glycation end products, vascular hypoxia [94], and activation of the polyol pathway are thought to play major roles. Typical signs and symptoms depend on the organ affected, but include resting sinus tachycardia without sinus arrhythmia, orthostatic hypotension, delayed gastric emptying, diabetic diarrhea, constipation, erectile dysfunction, bladder dysfunction, hypoglycemia unawareness, distal hyperhidrosis or anhidrosis, facial sweating, and gustatory sweating. Cardiovascular autonomic neuropathy is life threatening and carries a high risk of mortality [2, 95, 96].
5.2. Epidemiology
The prevalence of autonomic neuropathy in type 1 diabetes populations varies widely depending on duration of diabetes and method of assessment, with prevalences ranging from 2.6% in individuals with short duration of diabetes [97] to 90% in pancreatic transplant candidates [98]. Defining autonomic neuropathy based on an abnormal heart rate response to deep breathing and the presence of at least two autonomic neuropathy symptoms, the prevalence ranged from 3.7% to 11.3%, with a decreasing trend with higher BMI, in the Pittsburgh Epidemiology of Diabetes Complications (EDC) when the mean duration of diabetes was approximately 20 years [96]. In a subgroup of this same cohort twenty years later, when mean diabetes duration was 40 years, the prevalence of autonomic neuropathy based on an abnormal response to deep breathing was 61% [99]. In the entire EDC cohort, the incidence of autonomic neuropathy based on an abnormal heart rate response to deep breathing and the presence of at least two autonomic neuropathy symptoms was 0.78 per 100 person years of duration of diabetes, with a lower incidence for a given duration of diabetes in more recently diabetes diagnosed cohorts in the Pittsburgh Epidemiology of Diabetes Complications study [100]. In the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications study population, which because of inclusion criteria was a healthier cohort at study baseline than the EDC population, the prevalence of autonomic neuropathy at the follow-up years 13/14 of Epidemiology of Diabetes Interventions and Complications study, representing approximately 27 years of duration of type 1 diabetes, was 29% and 35% in the former intensively treated and conventionally treated Diabetes Control and Complications Trial participants [10]. The presence of diabetic autonomic neuropathy is associated with poor prognosis. In the EDC study, mortality during 20 years of follow-up was increased 2.43-fold after controlling for age, sex, BMI, and other late complications [96].
5.3. Pathophysiology
Diabetic autonomic neuropathy is a neuropathic disorder of the peripheral nervous system in individuals with diabetes or prediabetes. The pathogenesis of diabetic autonomic neuropathy is poorly understood, but long exposure to hyperglycemia [94, 101], advanced glycation end products [2, 94, 101], vascular insufficiency [2, 94], and activation of the polyol pathway [2, 94, 101] have been long thought to play major roles. The nerves of the autonomic nervous system innervate every organ of the body and as such any organ system can be affected by diabetic autonomic neuropathy. Disorders resulting from damage to autonomic nerve fibers are typically classified into the following syndromes: cardiovascular autonomic neuropathy (CAN), gastrointestinal, genitourinary, hypoglycemia unawareness, and sudomotor.
5.3.1. Pathogenesis
Long exposure to hyperglycemia is one of the strongest hypotheses on the etiology of diabetic peripheral neuropathy. In individuals with type 1 diabetes, results from the Diabetes Control and Complications Trial showed significantly lower declines in the R-R interval over time in those in the intensive therapy arm of the trial [97]. Whether this was due to lower levels of hyperglycemia was not specified. There was a low incidence of CAN in both treatment arms (4% in the intensive group and 9% in the conventional group), with a 45% lower incidence in the treatment arm [10]. Follow-up of the entire cohort thirteen to fourteen years after the close-out of the trial revealed a marked increase in the prevalence of CAN in the entire cohort, which was significantly greater in the former conventional therapy group. Differences in HbA1c accounted for the majority of the group differences in the incidence of CAN [102]. The beneficial effect of former intensive therapy on the incidence of neuropathy appeared to be greater for CAN than for distal symmetrical polyneuropathy, suggesting that the detrimental effect of hyperglycemia may be greater on small nerve fibers than large nerve fibers [10]. Mechanisms by which hyperglycemia may cause nerve damage include activation of the polyol pathway and accumulation of advanced glycation end products [2, 94, 101].
5.3.2. Cardiovascular Autonomic Neuropathy (CAN)
Cardiovascular autonomic neuropathy results from damage to the nerves that innervate the heart and coronary blood vessels. Because of its clinical importance, it has been the most studied of all of the diabetic autonomic neuropathy syndromes. It is the most life threatening of all of the diabetic autonomic neuropathy syndromes and carries a high risk of mortality. Signs/symptoms of CAN include orthostatic hypotension, sinus tachycardia, exercise intolerance, silent myocardial infarction, and sudden death.
Autonomic nervous system innervation of the heart largely regulates heart rate variability. In diabetes, cardiac autonomic nervous system dysfunction generally progresses from the apex to the base of the heart [103]. Diabetic autonomic neuropathy appears to affect the long nerve fibers first [2]. In CAN, autonomic dysfunction is usually observed first as a decrease in parasympathetic activity, reflecting damage to the vagal nerve, the longest of the autonomic nerve fibers, and a compensatory increase in sympathetic autonomic nervous system activity [103]. Sympathetic activity increases heart rate while parasympathetic activity decreases heart rate. The decline in parasympathetic activity is reflected in the decline in variation in heart rate with inspiration and expiration, where there is less of a decline in heart rate with expiration. A decline in heart rate variability is one of the earliest manifestations of CAN [103]. This compensatory increase in heart rate with parasympathetic denervation also manifests in an increased resting heart rate, and rates may reach greater than 100 beats per minute [103], resting sinus tachycardia.
Autonomic innervation of the heart also regulates blood pressure. The apparent early vagal denervation in CAN results in increased sympathetic nervous system activity, partially due to the counter-regulatory activity of the parasympathetic neurons, increasing blood pressure. During sleep, this is reflected in the “non-dipping” pattern of blood pressure often observed in individuals with type 1 diabetes [104, 105]. This lack of nocturnal bradycardia is associated with prolongation of the heart rate corrected Q-T interval in adolescents with type 1 diabetes [106], although Stella et al [105] observed no cross-sectional association between “non-dipping” and CAN in adults with type 1 diabetes. Later cardiac sympathetic denervation results in loss in the normal heart rate and blood pressure responses to exercise. The normal increase in heart rate and blood pressure and subsequent increased cardiac output is impaired, reducing exercise tolerance [2, 103]. Sympathetic cardiac denervation also manifests as orthostatic hypotension, a prolonged drop in blood pressure upon standing due to reduced baroreceptor stimulated sympathetic increase in heart rate and vasoconstriction of splanchnic vascular beds. Orthostatic hypotension may often be asymptomatic, but can result in dizziness, syncope, falls and fractures.
CAN is associated with silent myocardial ischemia and infarction [2, 107], and carries a high risk of mortality [95, 96]. The association of diabetic CAN with silent myocardial infarction is likely due to the higher frequency of silent myocardial ischemia in individuals with diabetic CAN [2]. Damage to the myocardial sensory afferent fibers may reduce the sensation of ischemic pain [2]. A meta-analysis of twelve studies of individuals with diabetes showed a 2-fold higher risk of silent ischemia in those with CAN [2]. In a population of middle-age and elderly individuals with type 1 diabetes, poorer cardiac autonomic function predicted future coronary heart disease events [108]. Perhaps due to its association with silent myocardial ischemia, cardiovascular disease, resting tachycardia, and exercise intolerance, CAN greatly increases the risk of sudden death [109-111]. We have shown in individuals with long-standing type 1 diabetes that CAN as diagnosed based on heart rate variability and in the presence of at least one other symptom of autonomic neuropathy was a significant predictor of mortality, independently of distal symmetrical polyneuropathy and other late complications of diabetes [96].
5.3.3. Gastrointestinal autonomic neuropathy
Diabetic autonomic neuropathy affecting the gastrointestinal system may result in gastroparesis, esophageal dysfunction, diarrhea, fecal incontinence, or constipation. Gastroparesis, or delayed gastric emptying, is common in type 1 diabetes, with prevalence rates from approximately 30 to 50% [4, 112-114] and appears to be more prevalent in type 1 than in type 2 diabetes [115]. Symptoms of gastroparesis include nausea, vomiting, anorexia, bloating, early satiety, and wide swings in blood sugar [112]. hyperglycemia delays gastric emptying [116] while hypoglycemia accelerates it [117]. Esophageal dysfunction is thought to result from a combination of impairment of vagal nerve and enteric nervous system innervation of esophageal smooth muscle cells regulating peristalsis [117]. Symptoms of esophageal dysfunction include difficulty swallowing (dysphagia) and heartburn. Peristalsis dysmotility of the lower gastrointestinal track can result in diarrhea or constipation, both very commonly observed in type 1 diabetes. The diarrhea may be due to bacteria overgrowth resulting from bowel stasis, very rapid peristalsis, or both. Very slow peristalsis activity may result in constipation. Fecal incontinence results from poor anal sphincter tone and impaired rectal sensation [2].
5.3.4. Genitourinary autonomic neuropathy
Autonomic nerve dysfunction or damage affecting the genitourinary system may manifest as erectile and/or ejaculation dysfunction or failure in males, dyspareunia in females, and bladder dysfunction, in both genders. Autonomic neuropathy affecting the reproductive organs manifests as erectile and ejaculation failure in males and reduced sexual arousal, reduced vaginal lubrication and painful intercourse in females. Autonomic neuropathy affecting the urinary tract may result in decreased frequency of urination and increased urinary tract infections, increased post void residual volume, dribbling, and urinary incontinence [118, 119].
Erectile dysfunction in diabetes may be due to one or any combination of the following: neuropathy, atherosclerosis, changes in corporal erectile tissue including deposition of AGEs, anti-hyperglycemic medications, and psychological factors, although neuropathy appears to be the predominate cause [119]. The corpus cavernosum is innervated by both sympathetic and parasympathetic nerve fibers and sensory and somatic nerve fibers [120, 121]. The neurogenic basis of erectile dysfunction is a decrease in smooth muscle relaxation of the corpus cavernosum [119, 122], inadequate nitric oxide synthase activity [119, 122], impaired sensation of the glans penis [119, 120], and abnormal motor function of erectile tissue [119].
Little is known about the pathogenesis of sexual dysfunction in women. It is characterized by reduced sexual arousal, atrophic vaginitis and subsequent painful intercourse. It is poorly related to glycemic control, age, duration of diabetes, or diabetes complications [123], but appears to be related to depression and to improve with estrogen creams [118]. In a substudy of the Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications cohort examining female sexual dysfunction in 424 women with type 1 diabetes and a mean age of 42.8 years, the prevalence of female sexual dysfunction was 35% [124].
Bladder dysfunction is one of the most common complications of diabetes, affecting a large proportion of the type 1 diabetic population [117] and occurring early in the disease process. The diabetic neurogenic bladder is caused by degeneration of both afferent myelinated and efferent non-myelinated nerve fibers to the bladder. Afferent nerve fiber degeneration results in reduced sensation of a full bladder [125]. Efferent nerve fiber degeneration results in reduced frequency of micturition, incomplete emptying of the bladder, i.e. increased post-void residual volume, and eventually urinary incontinence [125]. The neurogenic bladder is associated with recurrent urinary tract infections [125] and may lead to renal failure/disease.
5.3.5. Hypoglycemia unawareness and associated autonomic failure
Autonomic neuropathy is associated with more severe hypoglycemic events [126, 127] and the loss of symptoms prompting awareness of hypoglycemia [128, 129]. However, the jury is still out on whether autonomic neuropathy actually causes a loss of counter-regulatory responses to hypoglycemia [130]. Hypoglycemia associated autonomic failure (HAAF) can occur in the absence of autonomic neuropathy [126, 131, 132]. Conversely, diabetic autonomic neuropathy is observed in the absence of hypoglycemia symptom loss [131, 133]. Additionally, reversal of hypoglycemia symptom awareness is observed after strict avoidance of hypoglycemia for a relative short period of times, i.e. several weeks to months [134-136]. This would all appear to suggest that autonomic neuropathy is not a causative factor in hypoglycemia unawareness, i.e. the loss of the counter-regulatory responses to hypoglycemia. However, in the presence of autonomic neuropathy and in combination with HAAF a greater reduction in counterregulatory response hypoglycemia is observed than in hypoglycemia unawareness without autonomic neuropathy [130]. Furthermore, the recovery of hypoglycemia awareness symptoms with strict avoidance of hypoglycemia is not as complete in those with autonomic neuropathy [128]. Even with the recovery of awareness symptoms, the epinephrine response to hypoglycemia is only partially recovered and even less so in those with autonomic neuropathy [130]. In aggregate, this suggests that autonomic neuropathy is not the predominate cause of hypoglycemia unawareness but does enhance its severity and may play a partial etiologic role.
5.3.6. Sudomotor autonomic neuropathy
Abnormalities in thermoregulation are common in type 1 diabetes [137, 138]. The sweat glands are innervated by sudomotor postganglionic unmyelinated sympathetic c-fibers. Autonomic neuropathy affecting sudomotor nerve function results in both anhidrosis and hyperhidrosis. Sudomotor dysfunction manifests symptomatically as dry scaly skin of the limbs and appendages, heat intolerance, and gustatory sweating. With increasing duration of diabetes, anhidrosis becomes more severe, progressing in a distal to proximal direction [118]. Gustatory sweating, in which there is excessive sweating in the face and trunk in response to eating is thought to result from imperfect reinnervation of postganglionic sudomotor C-fibers following denervation [118].
5.4. Assessment
Assessment of cardiovascular autonomic nervous system function can be done by measuring heart rate variability, the heart rate response in postural change from lying or sitting to standing, the blood pressure change from lying or sitting to standing, and the diastolic blood pressure response to a sustained hand grip. Heart rate variability can be assessed my measuring the heart rate response to paced deep breathing, the Valsava maneuver, and spectral analysis. The heart rate response to deep breathing and the heart rate response to a change in posture to the standing position predominately reflect parasympathetic function [2]. The heart rate response to the Valsalva maneuver reflects both parasympathetic and sympathetic function fairly equally [2]. The change in blood pressure from a lying or sitting position to a standing position and the blood pressure response to a sustained hand grip reflects sympathetic nervous system function [2].
Assessment of autonomic neuropathy affecting the gastrointestinal track can be done by endoscopy and scintographic measurement of esophageal bolus transit time for esophageal dysfunction; scintography, isotope breath tests, and ultrasonography for gastroparesis; hydrogen breath test for diabetic diarrhea; barium enema for constipation; and anorectal manometry, endoanal ultrasonography, colon transit tests, digital examination of the rectum, protoscopy and sigmoidoscopy for fecal incontinence [2, 139].
Erectile dysfunction can be assessed by taking a case history, such as with the International Index of Erectile Dysfunction, by physical examination including examining of external genitalia, blood tests including measurement of testosterone levels, measurement of nocturnal penile tumescence, and Doppler studies [2, 117, 140]. The Female Sexual Function Index has been used to evaluate sexual dysfunction in women with type 1 diabetes [124]. Vaginal plethysmography has also been used to directly assess vaginal lubrication in women with diabetes [141].
Post void residual volume can be assessed by transurethral catherization or non-invasively via ultrasound [142]. Bladder sensation and upper urinary tract dilation can be assessed with cystometry and voiding cystometrogram. Uroflometry can be used to assess urinary flow rate and sphincter function. A urine culture should also be done to assess bacteria cystitis. In women, a urogynecological examination should be done in order to exclude pelvic prolapse.
Assessment of sudomotor function can be done with the Quantitative Sudomotor Axon Reflex Test (QSART), thermoregulatory sweat test, or the sympathetic skin response. The thermoregulatory sweat test can be used to assess the pattern and distribution of anhydrosis [143]. The QSART is used to assess postganglionic sudomotor nerve function [119, 143]. The sympathetic skin response assesses postganglionic sudomotor sympathetic nerve fibers [144].
5.5. Management
Treatment and management of diabetic autonomic neuropathy includes tight glycemic control [4]; however, the primary focus is on alleviation of symptoms [4, 101]. Management of orthostatic hypotension consists of educating the patient in strategies to avoid or address reversible causes of hypotension, increased fluid and salt consumption supplemented with mineralocorticoid therapy, pharmacotherapy with sympathomimetic agents, and wearing clothing such as compression stockings that increase venous return [2, 101, 118]. Antioxidants and cardioselective beta-blockers may be beneficial in cardiac autonomic neuropathy [2].
For patients with esophageal dysmotility, proton pump therapy is conventionally used [119]. Fluid consumption immediately after consumption of medications should be advised in order to avoid pill-induced esophagitis in these patients [119]. Diets low in fat and soluble fiber may be beneficial in patients with gastroparesis [2, 119], although pharmacotherapy with prokinetic agents is the mainstay of therapy [119]. Insulin pump therapy may also help to improve symptoms in type 1 diabetic patients with gastroparesis [119]. Antibiotic therapy is beneficial in the treatment of diarrhea [2, 119].
Treatment of bladder dysfunction may be behavioral, pharmacological, or surgical. Behavioral management includes pelvic floor exercises to strengthen the muscles of the pelvic floor that support the bladder and urethretha. It also includes a program of scheduled fluid intake and micturition, manual procedures such as the Crede’s maneuver, pelvic tapping, the Valsava maneuver, and clean intermittent self-catheterization. Pharmacotherapy includes the use of antimuscarinic agents, cholinergic agents, and tricyclic antidepressants. In cases refractory to non-pharmacological and pharmacological treatment, surgical procedures such as vesicle neck resection, selective pudendal nerve block, unilateral pudendal neurectomy, and sacral neuromodulation may be beneficial [2, 119, 142, 145].
Treatment and management of erectile dysfunction should include psychological counseling; however, pharmacotherapy with the PDE5 inhibitors (sildenafil, vardenafil, tadalafil) is the mainstay of therapy. Intracavernous or intraurethral injections with vasoactive medication, vacuum constriction devices, and penile prosthesis implantation are also options [2, 119]. Vaginal estrogen creams in has been shown to be beneficial in diabetic women with female sexual dysfunction [118].
6. Conclusion
Peripheral and autonomic neuropathy is a common complication of type 1 diabetes with significant morbidity and mortality. Fortunately, aggressive hyperglycemia control can delay the onset and minimize the severity of neuropathy in this population. The pathophysiology of neuropathy is complex and likely involves multiple mechanisms, which may be the reason for lack of efficacious treatments beyond glucose control. Early recognition of peripheral and autonomic neuropathy is also important to decrease amputation risk and mortality.
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Peltier",slug:"amanda-c.-peltier",email:"amanda.peltier@vanderbilt.edu",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Vanderbilt University Medical Center",institutionURL:null,country:{name:"United States of America"}}},{id:"155823",title:"Dr.",name:"Baqiyyah",middleName:null,surname:"Conway",fullName:"Baqiyyah Conway",slug:"baqiyyah-conway",email:"baqiyyah@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Vanderbilt University",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Classification ",level:"1"},{id:"sec_3",title:"3. Diabetic distal symmetric polyneuropathy in type 1 diabetes mellitus",level:"1"},{id:"sec_3_2",title:"3.1. Overview",level:"2"},{id:"sec_4_2",title:"3.2. Diagnostic criteria",level:"2"},{id:"sec_5_2",title:"3.3. Epidemiology",level:"2"},{id:"sec_6_2",title:"3.4. Pathophysiology",level:"2"},{id:"sec_7_2",title:"3.5. Assessment",level:"2"},{id:"sec_8_2",title:"3.6. Management",level:"2"},{id:"sec_9_2",title:"3.7. Treatment of neuropathic pain",level:"2"},{id:"sec_11",title:"4. Focal neuropathies",level:"1"},{id:"sec_11_2",title:"4.1. Overview and epidemiology",level:"2"},{id:"sec_12_2",title:"4.2. Pathophysiology",level:"2"},{id:"sec_13_2",title:"4.3. Assessment",level:"2"},{id:"sec_14_2",title:"4.4. Treatment",level:"2"},{id:"sec_16",title:"5. Diabetic autonomic neuropathy",level:"1"},{id:"sec_16_2",title:"5.1. Overview",level:"2"},{id:"sec_17_2",title:"5.2. Epidemiology",level:"2"},{id:"sec_18_2",title:"5.3. Pathophysiology",level:"2"},{id:"sec_18_3",title:"5.3.1. Pathogenesis",level:"3"},{id:"sec_19_3",title:"5.3.2. Cardiovascular Autonomic Neuropathy (CAN)",level:"3"},{id:"sec_20_3",title:"5.3.3. Gastrointestinal autonomic neuropathy",level:"3"},{id:"sec_21_3",title:"5.3.4. Genitourinary autonomic neuropathy",level:"3"},{id:"sec_22_3",title:"5.3.5. Hypoglycemia unawareness and associated autonomic failure",level:"3"},{id:"sec_23_3",title:"5.3.6. Sudomotor autonomic neuropathy",level:"3"},{id:"sec_25_2",title:"5.4. Assessment",level:"2"},{id:"sec_26_2",title:"5.5. Management",level:"2"},{id:"sec_28",title:"6. Conclusion",level:"1"}],chapterReferences:[{id:"B1",body:'Dyck PJ, Albers JW, Anderson H, Arezzo JC, Biessels GJ, Bril V, et al. Diabetic Polyneuropathies: Update on Research Definition, Diagnostic Criteria and Estimation of Severity. Diabetes Metab Res Rev. 2011. Epub Jun 21, 2011.'},{id:"B2",body:'Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic Autonomic Neuropathy. Diabetes Care. 2003;26:1553-79.'},{id:"B3",body:'Coppini DV, Bowtell PA, Weng C, Young PJ, Sonksen PH. Showing neuropathy is related to increased mortality in diabetic patients-a survival analysis using an accelerated failure time model. 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Diabetologia. 1994;37:1265-76.'},{id:"B135",body:'Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA. Restoration of hypoglycaemia awareness in patients with long-duration of insulin-dependent diabetes. Lancet. 1994;344(8918):283-7.'},{id:"B136",body:'Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes. 1994;43:1426-34.'},{id:"B137",body:'Hoeldtke RD, Bryner KD, Horvath GG, Phares RW, Broy LF, Hobbs GR. Redistribution of sudomotor responses is an early sign of sympathetic dysfunction in type 1 diabetes. Diabetes. 2001;50(2):436-43.'},{id:"B138",body:'Maggs DC, Macdonald IA, Tattersall RB. Thermoregulatory responses to hyperinsulinaemic hypoglycaemia and euglycaemia in IDDM. Diabetologia. 1994;37(7):689-96.'},{id:"B139",body:'O\'Donovan D, Samson M, Feinle C, Jones KL, Horowitz M. Diabetic Autonomic Neuropathy: Gastrointesitnal Tract. In: Gries FA, Cameron NE, Low PA, Ziegler D, editors. Textbook of Diabetic Neuropathy. New York, New York: Thieme; 2003. p. 246-62.'},{id:"B140",body:'Stief CG, Ziegler D. Diabetic Autonomic Neuropathy: Urogenital System. In: Gries FA, Cameron NE, Low PA, Ziegler D, editors. Textbook of Diabetic Neuropathy. Stuttgart, Germany: Georg Thieme Verlag; 2003. p. 262-78.'},{id:"B141",body:'Wincze JP, Albert A, Bansal S. Sexual arousal in diabetic females: physiological and self-report measures. Arch Sex Behav. 1993;22(6):587-601.'},{id:"B142",body:'Dorsher PT, McIntosh PM. Neurogenic Bladder. Adv in Urol. 2012. Epub February 8, 2012.'},{id:"B143",body:'Low PA. Postural Hypotension and Anhydrosis. In: Veves A, Malik RA, editors. Diabetic Neuropathy: Clinical Management. 2nd ed. Totowa, New Jersey: Humana Press, Inc.; 2007. p. 413-32.'},{id:"B144",body:'Kucera P, Goldenberg Z, Kurca E. Sympathetic skin response: review of the method and its clinical use. Bratisl Lek Listy. 204;105(3):108-16.'},{id:"B145",body:'Golbidi S, Laher I. Bladder dysfunction in diabetes mellitus. Frontiers in Pharmacology. 2010 November 16, 2010;1.'}],footnotes:[{id:"fn1",explanation:"*The DCCT was a groundbreaking study of patients with type 1 diabetes in the United States; a large, multicenter study designed to test whether improved glycemic control delayed the onset or progression of diabetic complications. The follow up epidemiologic study, EDIC (Epidemiology of Diabetes Interventions and Complications) continued to follow the same patients enrolled in DCCT, which is still ongoing. "}],contributors:[{corresp:"yes",contributorFullName:"Baqiyyah Conway",address:"baqiyyah@yahoo.com",affiliation:'
Department of Epidemiology, School of Public Health, West Virginia University, Morgantown, West Virginia, USA
Division of Neurology, Department of Medicine, Vanderbilt University, Nashville, TN, USA
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1. Introduction
Water is essential for sustaining life, yet it is also the source of many diseases for living things [1]. With the increase in population and the development of industrial activities, surface water resources and groundwater have become increasingly polluted. Thus, humans are exposed to many chemicals found in drinking water.
Several chemicals (organic and inorganic) have been identified in drinking water, and the sources of pollution of the drinking water system are multiple [2]. Among these pollutants, the literature reports particularly chlorine disinfection by-products [3, 4, 5], fluorine [6, 7, 8], lead [9, 10] chromium [11, 12, 13], cadmium [14, 15], nitrates [16, 17], pesticides [18, 19], hardness [20, 21], arsenic [22, 23], etc. The presence of chemical substances in the municipal drinking water is a major health concern. Indeed, some substances detected in drinking water have been the subject of epidemiological studies [1]. The health effects reported in the literature are different cases of cancer, reproductive problems (malformations) cardiovascular and neurological diseases. Drinking water is therefore an important route of exposure to chemicals.
Pollutants, particularly heavy metals are released into the environment from a wide spectrum of natural and anthropogenic sources [24]. Heavy metals are omnipresent in the environment, occurring in varying concentrations in air, bedrock, soil, water, and all biological matter [25, 26]. The principal anthropogenic sources are industrial and urban effluents, runoff water, drinking water production and distribution equipment and drinking water treatment processes [1]. The presence of heavy metals in the environment constitutes a potential source of both soil and groundwater pollution.
In Haiti, the work carried out in the field of the physicochemical quality of water intended for pollutants such as: lead, chromium [27], fluorine [28]. Excessive concentrations of hardness have also been observed in water resources [29]. These concentrations of natural origin are added to those generated by anthropogenic actions, such as poor management of solid waste, the absence of urban sanitation networks and water treatment plants only increase the rate of human exposures to these pollutants. These exposures to chemical substances continue to put Haitians at risk, and several examples shed light on the realities of risk management with respect to toxic chemicals in developing Countries [30]. The fact that the hydrographic basin of Port-au-Prince consists mainly of karst aquifers [31], rainwater, polluted by atmospheric particles of substances originating from industrial activities, and urban wastewater feeds, through the dominant geology, groundwater, thus leading to suppose that the water resources of this region are subject to significant chemical pollution.
The impact on human health of natural materials such as water, rocks and minerals has been known for thousands of years, but there have been few systematic and multidisciplinary studies on the relationship between geologic materials and processes and human health (the field of study commonly referred to as medical geology) [32]. In order to achieve a better understanding in urban and rural areas of Haiti of the different routes of exposure and the causes of a number of environmental health problems generated by exposure to high concentrations of essential and non-essential chemicals for the organism that are detected in drinking water, it seems relevant that geoscientists, environmental and health science researchers; as well as public health specialists combine their skills to approach the problem of pollution of water intended for human consumption by taking into account the two main sources of the qualitative degradation of water: “geological contributions and anthropogenic actions”. The aim of this study is: (i) to analyze the contribution of geology and anthropogenic actions in the alteration of water quality, (ii) to review the toxicology of chemicals detected in water distributed in Port-au-Prince.
2. Medical geology and environmental health in the geographical context of Port-au-Prince
2.1 Environmental health and assessment of health risks associated with chemical mixtures in drinking water
During the 1950s, forms of anxiety gradually manifested themselves regarding the state of environmental degradation and its harmful consequences for the survival of ecosystems and for development [33]. Indeed, since the said decade, the environment-human health relationship has become a major concern in the field of public health. The questions of contaminated soil, emanations from landfills, destruction of the ozone layer, global warming, food contamination, radiation emitted by household appliances, new biological hazards … are among the subjects of intervention by government authorities [34].
Abenhaim [35] argues “Environmental health issues are among the most complex for scientists to study and the most difficult for policy makers to resolve. First, because it is rare that the exhibitions are pure, thus leaving room for many confounding factors. Then, because the contaminations are generally in relatively small quantity, at the limits of the observable effects. Finally, because the consequences of exposure often occur over the long term” [35]. Exposure to chemical mixtures is a reality that would seem to dictate the need to pay much attention to hazard identification, exposure assessment and risk characterization [36], of mixtures in water intended for human consumption. Contrary to this environmental reality, the toxicological reality is that until recently most of the research carried out in this field has been devoted to studies on the effects of substances acting independently, without considering the interactions or combined effects between pollutants at the inside the human organism [37].
In Haiti, all the work carried out on the health risk linked to the pollution of drinking water by chemical substances, the risk characterization was made based on the independent effects of the pollutants studied. This approach provides information on the level of exposure of the population to a substance but does not make it possible to assess the interactions of the various pollutants detected in the distributed water. It is now widely recognized that studying the combined effects of chemical mixtures in drinking water is an integral part of public health [37]. Characterizing the combined actions of chemical mixtures involves the challenge of how to define the antagonistic, additive, or synergistic effect. It is therefore important to understand the terminology that describes the combined effect of the agents in terms of the mechanism of action. Seventy years ago, three basic concepts of common action or the interaction of the combination of chemicals were defined by biomathematicians [38, 39, 40] and they are still valid today.
Indeed, Bliss [38] identified three modes of action of constituents within a mixture vis-à-vis living organisms:
“Independent joint action”: in this type of action, the constituents act on different sites of action and the biological response of one constituent is not influenced by another.
“Similar joint action”: the constituents act on the same sites of action and the biological response of one constituent is not influenced by another. This is the approach most used for the study of mixtures.
“Synergistic action”: where the response of a mixture cannot be known by the isolated responses of the constituents. The response of a mixture depends on the combined effects of its constituents.
All three basic principles of common action of pollutants are theoretical. However, these concepts will most likely need to be addressed at the same time, especially when the mixtures consist of more than two compounds and when the targets (individuals rather than cells) are more complex.
Fox et al. [41] considers the risk assessment of chemical mixtures or the cumulative risk assessment (CRA) as the most recent step in the evolution of assessment. USEPA [42, 43] defines this approach as an analysis, characterization, and possible quantification of the combined risks to human health or the environment due to multiple substances or stressors. This definition suggests that additivity is the initially accepted mode of action for the implementation of ERC.
U.S. EPA [44] developed for the implementation of cumulative risk assessment, the Hazard Index (HI) method. This approach first assesses the effects of a substance acting independently of the others. HI is calculated by dividing the measured or estimated exposure concentration by the reference concentration (RfC):
HI=Measured or estimated exposure concentration/RfC
For HI < 1, the exposure concentration is below the cutoff value, so no health effect can be expected. On the other hand, for HI ≥ 1, the exposure concentration exceeds the threshold value, further research on the health effects of the pollutant is recommended, by calculating the Hazard metric HM.
HM=Measured or estimated exposure concentration/NOAEL or adjusted LOAEL
Based on the additive action of pollutants, the application of the HI or HM model to assess the concentration of exposure due to chemical mixtures can be also expressed:
LCE=C1M1+C2M2+CnMn≤1E1
LCE: Limit of exposure concentration
C1, C2 and Cn: observed concentrations.
M: Maximum acceptable concentration (threshold value)
In the distribution units where chlorination is applied to raw water rich in organic matter, a quite common situation or process in Haiti, the populations served are exposed to a certain number of chemical substances (by example Disinfection by-products (DBPs)), very known for their adverse effects on human health, especially the occurrence of cancers [45, 46]. In the absence of national standards for the quality of drinking water, Haiti applies the guidelines of the World Health Organization. The application of the HI or HM model in the evaluation of the combined effects of by-products could be, in a simplified manner, carried out from:
TSWHO: WHO threshold value Different types of complex mixtures require different approaches, and the usefulness of a certain approach depends on the context in which one is confronted with a mixture, and on the amount, type and quality of the available data on the chemistry and the toxicity of the mixture [47]. Scientific literature reports the occurrence of several detected in drinking water in Haiti [26, 27, 28, 29]. Moreover, MSPP and WHO [48] note “the quality of water intended for human consumption is not subject to any control. In such a context, the study of the combined effects of several chemical substances in drinking water and the assessment of the risks generated for human health constitute an important topic of transdisciplinary public health research.
2.2 Medical geology and ONE HEALTH approach in health risks assessment of drinking water in Haiti
Located between 18° and 20°6’ Northern latitude and between 71°20′ and 74°30’ Western longitude, Haiti divides with Dominican Republic “the island of Hispaniola” which is the second biggest island of the Caribbean. Its capital, Port-au-Prince, is settled at the bottom of the Gulf of “La Gonâve”, in the south border of Plain of Cul-de-sac and in the north catchment area of the “Massif de la Selle” piedmont (Figure 1). The main municipalities which constitute urban community of Port-au-Prince are Port-au-Prince, Delmas, Pétion-ville, Croix-des-bouquets, Gressier and Carrefour.
Figure 1.
Map of the west department of Haiti and metropolitan area of Port-au-Prince [49].
Haiti is exposed to a considerable ecological imbalance, characterized by catastrophic flooding associated to torrential rains and hurricanes, devastating earthquakes, and deforestation [50]. Other problems, resulting from this imbalance include land use forming the immediate perimeter of headwaters and wells, wetlands draining, arable soils erosion, the decrease of the headwaters flow and groundwater, seawater intrusion, sewers obstruction and fecal pollution [51]. In addition, Haiti is one of the most vulnerable countries to climate change [52]. In general, Haiti’s geophysical environment is characterized by rugged relief. Most of the territory is occupied by mountains formed of limestone and karst aquifers [31, 53, 54, 55]. The existence of karst aquifers conditions in rainy weather the contamination of groundwater by surface pollution. Indeed, the main characteristics of karst aquifers are the existence of irregular networks of pores, cracks, fractures and pipes of various shapes and sizes. Such a structure, of significant physical and geometric heterogeneity, causes complex hydraulic conditions and the spatial and temporal variability of hydraulic parameters. After a downpour, rapid and turbulent groundwater recharge occurs through drainage in large conduits with high volume of unfiltered water [56].
Groundwater resources at Port-au-Prince are vulnerable to contamination related to polluted water infiltration such as leachates, cesspools and septic tanks, stormwater runoff, waste oil discharging, over-irrigation and industrial discharging [50]. These sources of groundwater recharge may contain organic and inorganic compounds which can be in dissolved and colloidal forms or associated to particles. Microbiological and physicochemical characterization of groundwater resources in the metropolitan area of Port-au-Prince, among other things, highlight the presence of heavy metals [57], fecal coliforms [27] and Cryptosporidium oocysts [58]. In addition to bacterial and metal contaminations, it was found that aquifers in Haiti are also exposed to seawater pollution [50]. According to Gonfiantini and Simonot [59], the salt water is slightly enriched with heavy isotopes with respect to fresh groundwater, not showing any deviation from the straight line of meteoric waters. In the area of Port-au-Prince, the salinity of the groundwater is the result of seawater intrusion because of intensive exploitation [59].
The geophysical environment of Port-au-Prince, the inefficiency of the sanitation system (collection and treatment of solid waste, drainage, and treatment of wastewater, etc.), which contribute to the microbiological and physicochemical quality of the water distributed by public networks to the population gives rise to a particular epidemiological environment where the water generates several dangers for the health of consumers. In such a context, the assessment and management of health risks associated with water intended for human consumption require a multidisciplinary approach and call on researchers, technicians, and specialists in several fields of life and earth sciences as well as the humanities and social sciences.
The 2030 Agenda for Sustainable Development of the United Nations (UN) establishes goals and targets in areas of critical importance for humanity [60, 61], Ramirez-Mendoza et al., 2020 [62]. Indeed, the SDGs are linked to one another, the success of one often depending on the resolution of problems generally associated with another objective [60]. They thus constitute a universal and transversal approach concerning all countries, in the North as in the South. Regarding the issue of water, objective 6 - access to safe water and sanitation - aims to meet the challenges of drinking water, sanitation, and hygiene for populations, as well as issues concerning aquatic ecosystems. In the absence of quality and sustainable water resources and sanitation, progress in several other areas of the Sustainable Development Goals, including health, education and reduce of poverty, will also be delayed [60]. This objective, taken in the prism of the situation of the urban and hydrological context, as well as the geophysical environment of Haiti, raises concerns. However, the launching by public authorities and funding agencies of large research programs with the objective of generating and applying knowledge, promoting innovations in the life and earth sciences, as well as in human and social sciences, in a context of transdisciplinary would be of great use, even essential for the development to achieve the various objectives [63]. Indeed, Medical geology, the science that deals with the relationship between natural geological factors and human and animal health problems [32], and the One Health approach, an approach that attempts to bringing together medical/public health researchers, veterinary researchers, and environmental scientists to tackle health problems, provides an adequate theoretical framework to address environmental health problems resulting from the degradation of natural environment in Port-au- Prince.
The interconnectedness of human, animal, and environmental health is at the heart of One Health, an increasingly important prism through which governments, NGOs (nongovernmental organizations), and practitioners view human health) [64]. Mazet et al., [65] note “An important implication of the One Health approach is that integrated policy interventions that simultaneously and holistically address multiple and interacting causes of poor human health—unsafe and scarce water, lack of sanitation, food insecurity, and proximity between animals and humans—will yield significantly larger health benefits than policies that target each of these factors individually and in isolation. By its very nature, the One Health approach is transdisciplinary, since it is predicated on agricultural scientists, anthropologists, economists, educators, engineers, entomologists, epidemiologists, hydrologists, microbiologists, nutritionists, physicians, public health professionals, sociologists, and veterinarians working collaboratively to improve and promote both human and animal health” [65].
3. Chemistry and toxicology of selected pollutants detected in water distributed in Port-au-Prince
3.1 Presence of fluoride in drinking water and risk for human health
Fluoride, the 13th most abundant element in the earth’s crust, is essential to human life [66]. Elemental fluorine almost never occurs in nature, but fluoride is widely distributed in the Earth’s crust, mainly as the mineral’s fluorspar, cryolite, apatite, mica, hornblende, and fluorite [67, 68]. Table 1 shows certain physical and chemical properties of fluoride.
Fluoride participates in the formation of bones and teeth and contributes to their solidification. It enters the body in the form of fluorides through drinking water, food, air, drugs, and cosmetics. It is known to have beneficial and harmful effects on humans [69]. Indeed, its deficiency has long been linked to the incidence of dental caries [70], while prolonged excessive intake has been associated with fluorosis [71]. Large populations throughout parts of the developing world suffer the effects of chronic endemic fluorosis [70].
The most important source of fluoride intake in the human body is drinking water [72]. According to WHO [73], the guideline value for fluoride in drinking-water is 1.5 mg/L, based on increasing risk of dental fluorosis at higher concentrations and that progressively higher levels lead to increasing risks of skeletal fluorosis. This value is higher than that recommended for artificial fluoridation of water supplies for prevention of dental caries, which is usually 0.5–1.0 mg/L. WHO [74] recommends that, in setting a standard, Member States should consider drinking-water consumption and the intake of fluoride from other sources. Nevertheless, a content of 1 mg/l of fluoride ions is approximately the desirable concentration in the water supplied to the population to ensure optimal dental health [75]. However, several factors, including temperature, can influence this optimum value, which varies from one climatic region to another. It is therefore important to determine this optimal dose for each region depending on whether it is in a temperate zone or in a tropical zone [76]. Dean [77] has shown that the optimum concentration of fluorine as a function of the ambient temperature is 1.0–1.2 mg/l.
The optimal dose of fluoride in drinking water is defined as the amount of fluoride which decreases the prevalence of dental caries with the absence of significant fluorosis [78, 79, 80]. Fluorosis is the demineralization of tooth enamel by excessive fluoride ingestion during the years of tooth calcification [81]. This phenomenon, observed in children, can range from mild fluorosis to a severe manifestation Indeed, Dean [78] observed that 10% of children consuming water containing 1.0 mg/l of fluoride could develop benign fluorosis. It is reported in the literature that children living in the southwestern United States develop severe fluorosis, much more so than those living in the midwestern, while both groups are exposed to the supply systems. Water containing the same concentration of fluorine [82]. Other studies have suggested that the extremely high temperature of the southwest is a major factor contributing to the increase in demand for drinking water and the increase in severe and endemic dental fluorosis [80, 81, 82].
In Haiti, studies carried out on the water resources of the Center-Sud hydrographic region of Haiti (Figure 2), revealed fluorine concentrations between 0 and 2 mg/l [28, 83]. The various localities of this region are exposed to an average daily temperature ranging from 17 to 36° C.
Figure 2.
Map of the “Centre-Sud” hydrographic region of Haiti.
These observations lead on the one hand to questioning the problems of dental caries and fluorosis from which the populations of the areas studied may suffer and, on the other hand, to determine the optimal dose of fluoride in water intended for human consumption. of the Center-South hydrographic region of the Republic of Haiti. Fluoride’s exposure is a major public health problem particularly for children. Indeed, intake of high-water fluoride concentration during child’s growth and development stages has been associated with mental and physical problems [84, 85, 86].
3.2 Water hardness and human health
Hardness is the traditional measure of the capacity of water to react with soap and describes the ability of water to bind soap to form lather, which is a chemical reaction detrimental to the washing process [87]. Water hardness results from the contact of groundwater with rock formations. It is the sum of the concentrations of dissolved polyvalent metal ions which Ca2+ and Mg2+ are predominant. The sources of the metallic ions are typically sedimentary rocks, and the most common are limestone (CaCO3) and dolomite (CaMg(CO3)2) [66].
Ca and Mg are present as simple ions Ca2+ and Mg2+ with the Ca levels varying from tens to hundreds of mg/L and the Mg concentrations varying from units of tens of mg/L [88]. Magnesium is significantly less abundant than calcium in rocks and in most natural waters. In addition, magnesium concentrations are much lower in the water than calcium. They are generally less than 50 mg/L, although values higher or equal to 100 mg/L are stored particularly in cold climates [87]. The physical and chemical properties of Ca2+ and Mg2+ are presented in Table 2.
Physical and chemical properties of Ca2+ and Mg2+.
Hardness (in mg equivalent CaCO3/L) can be determined by substituting the concentration of calcium and magnesium, expressed in mg/L, in the following equation [89]:
Total hardness=2.497Ca2+mg/L+4.118Mg2+mg/LE3
Each concentration is multiplied by the ratio of the formula weight of CaCO3 to the atomic weight of the ion; hence, the factors 2.497 and 4.118 are included in the hardness relation [89].
Hardness is most expressed as milligrams of calcium carbonate equivalent per liter [90]. Water containing calcium carbonate at concentrations below 60 mg/l is generally considered as soft; 60–120 mg/l, moderately hard; 120–180 mg/l, hard; and more than 180 mg/l, extremely hard [91]. Although hardness is caused by cations, it may also be discussed in terms of carbonate (temporary) and non-carbonate (permanent) hardness [90].
Calcium and magnesium are essential for the human body [90]. They contribute to the formation and solidification of bones and teeth and play a role in the decrease of neuromuscular excitability, myocardial system, heart, and muscle contractility, intracellular information, transmission, and blood contractility [87, 88, 92]. They also play a major role in the metabolism of almost all cells of the body and interacts with many nutrients [93]. However, inadequate, or excess intake of either nutrient can result in adverse health consequences [90].
According to WHO [90] “Inadequate intakes of calcium have been associated with increased risks of osteoporosis, nephrolithiasis (kidney stones), colorectal cancer, hypertension and stroke, coronary artery disease, insulin resistance and obesity. Most of these disorders have treatments, but not cures. Owing to a lack of compelling evidence for the role of calcium as a contributory element in relation to these diseases, estimates of calcium requirement have been made based on bone health outcomes, with the goal of optimizing bone mineral density.
To a great extent, individuals are protected from excess intakes of calcium by a tightly regulated intestinal absorption and elimination mechanism through the action of 1,25-dihydroxyvitamin D, the hormonally active form of vitamin D. When calcium is absorbed more than need, the excess is excreted by the kidney in healthy people who do not have renal impairment” [90].
Magnesium is the fourth most abundant cation in the body and the second most abundant cation in intracellular fluid [90]. In the cardiovascular system, magnesium is the candidate element. It plays an important role as a cofactor and activator of more than 300 enzymatic reactions including glycolysis, ATP metabolism, transport of elements such as Na, K and Ca through membranes, synthesis of proteins and nucleic acids, neuromuscular excitability and muscle contraction [94]. That can have hand in various mechanism where the main is the calcium antagonist effect which can be direct or indirect [95].
Low magnesium levels are associated with endothelial dysfunction, increased vascular reactions, elevated circulating levels of C-reactive protein (a proinflammatory marker that is a risk factor for coronary heart disease) and decreased insulin sensitivity. Low magnesium status has been implicated in hypertension, coronary heart disease, type 2 diabetes mellitus and metabolic syndrome. Magnesium deficiency has been implicated in the pathogenesis of hypertension, with some epidemiological and experimental studies demonstrating a negative correlation between blood pressure and serum magnesium levels. However, data from clinical studies have been less convincing [90].
Indeed, water hardness has become an important public excess health issue [96]. Kobayaski [97] showed a relationship between water hardness and the incidence of vascular diseases. The scientific literature reported the existence of a relationship between cardiovascular disease mortality and water hardness [98, 99, 100]. Miyake and Iki [101] observed a lack of association between water hardness and coronary heart diseases mortality in Japan. Nonetheless, many studies covering many countries suggest such a correlation and geochemically it is worthy of serious study [88]. Based on available information in the literature on the association of water hardness and the incidence of cardiovascular diseases (CVD), Eisenberg [102] considered that Mg seems to be the basic element. Indeed, extremely hard natural water with CaCO3 concentration higher than 200 mg/l with a magnesium concentration lower than 7 mg/l may affect various organs including the cardiovascular physiology [87].
In Haiti, studies on the spring waters used to supply a part of the population of the Metropolitan Area of Port-au-Prince (MAPP), the most important urban area of the country, showed a total hardness greater than 200 mg/l, with magnesium concentration less than 7 mg/l [29]. In addition, magnesium concentrations ranging from 5.58 to 6.9 mg/l have been measured in groundwater in the metropolitan area of Port-au-Prince [103]. Drinking water low in Mg significantly increases the likelihood of cardiovascular mortality [104]. Catling et al., [105] found significant evidence of an inverse association between magnesium levels in drinking water and cardiovascular mortality following a meta-analysis of case control studies. In Haiti, cardiovascular disease (CVD) is now the leading cause of adult mortality in Haiti [106, 107].
3.3 Groundwater pollution by heavy metals and human health
Metals are natural constituents of the Earth’s crust. The distribution and fate of metals in the environment is governed by their properties and the influence of environmental factors [108]. In environmental compartments, heavy metals constitute an ecological and human health concern since heavy metals are not degraded biologically like certain organic pollutants [109]. Metals exert biological effects that can be beneficial or harmful. Many metals such as Fe, Cu, Co, Mn, Zn, and Cr are essential for humans, and deficiency states with clinical abnormalities have been identified [27, 108, 110]. Other metals such as Hg, Pb, Cd, and As are not known to be essential for any animals [110]. Essential elements can also cause toxic effects at high doses.
In Haiti, heavy metals (lead, chromium, and nickel) have been measured in groundwater [27]. The physical and chemical properties of these heavy metals are presented in Table 3.
Physical and chemical properties of chromium, lead and nickel.
3.3.1 Effects of chromium on human health
Chromium is one of the heavy metals considered a major pollutant. It has been widely used in industrial processes for leather tanning, dyes and paint preparation, textile manufacturing, paper mills, wood preservation, stainless steel production, and photography [111]. Chromium exists in several oxidation states. The most stable and common forms are trivalent chromium, Cr(III), and hexavalent chromium, Cr(VI), which exhibit contrasting biochemical properties and toxicokinetics [112, 113]. Cr(III) compounds occur naturally in the form of oxides, hydroxides or sulfates, and they are nutritionally necessary to humans for glucose, fat and protein metabolism [114]. In contrast, Cr(VI) compounds are mainly anthropogenic and highly toxic; its mutagenic and carcinogenic nature and high oxidation state enhances its ability to move into living cells [114]. Cr(III) and Cr(VI) interchangeability depends on their concentration in solution, pH, the redox potential (Eh) of the medium, and the presence or absence of a strong oxidant or reductant [111, 115].
The toxicity of chromium is directly dependent on the valence state, with hexavalent chromate Cr(VI) and trivalent chromate Cr(III) being of the greatest interest [112]. Oral bioavailability varies with valence state, with Cr(VI) being more readily absorbed. Cr(VI) can be broken down into Cr(III) within the acidic environment of the stomach [111]. Acute exposure to chromium is indicated by immediate irritation of the eye, nose, throat, and respiratory tract, which results in burning, congestion, epistaxis, and cough. Ulceration, bleeding, and erosion of the nasal septum mark chronic exposure. Cough, chest pain, dyspnea, and chromium-induced asthma indicate exposure to soluble chromium products [113]. If chronic exposure is suspected, in conjunction with weight loss, cough, and hemoptysis, this suggests the development of bronchogenic carcinoma. Dermatological manifestations include painless, slow-healing ulceration of the fingers, knuckles, and forearms. Ingestion is marked by nausea, vomiting, abdominal pain, prostration, and death associated with uremia [114].
3.3.2 Effects of lead on human health
Drinking water is one of the major sources of human exposure to lead [115]. Lead particularly targets the nervous system, blood, and kidney [116]. Many studies found associations between low level environmental Pb exposure and chronic kidney disease, a general term for heterogeneous disorders affecting the structure and function of the kidney (CKD) [117, 118]. Long-term lead exposure may generate irreversible functional and morphological renal changes [119], distal motor neuropathy and possibly seizures and coma [120]. Infants and small children are more sensitive to the effects of lead, which moreover is transported through the placenta to the foetus [121]. Lead accumulation in fetuses and small children might cause developmental disruption in terms of neurological impairment characterized by a decrease of cognitive faculties, which can be reversible or not, evaluated by psychomotor tests such as the verbal IQ (Intellectual Quotient) test [27, 109]. The period when IQ is most affected is from birth to about 4 years of age [122].
Scientific literature on lead water pollution reports “Lead remains a problem in drinking water in many parts of the world, with millions of properties served by distribution systems containing lead components. Strong links have been established between human exposure to lead and health effects in both adults and children. As a result, the allowable levels of lead indrinking water have generally become lower. Implementation of these regulations is difficult with the controls available. Future recommendations for aspiring to zero lead in drinking water are: (i) improving sampling, monitoring and modeling; (ii) Wider application of short-term pointof- use devices; (iii) replacement of all lead pipes and plumbing through applicable regulations and increased awareness public” [123, 124, 125, 126].
3.3.3 Effects of nickel on human health
Nickel is insoluble in water. However, when it is in the form of exceptionally fine particles, it ionizes as Ni (II) in water and in body fluids such as blood. During oral exposure, the major effects observed are the death of a child after ingestion of 570 mg of nickel/kg [127] and intestinal disorders such as nausea, abdominal cramps, and diarrhea [128]. Immunological, hematological, hepatic, renal, genotoxic effects on embryonic development and reproduction have been reported depending on the route of entry into the body [129].
4. Conclusion
The aim of this study is: (i) to analyze the contribution of geological factors and anthropogenic actions in the alteration of water quality in Port-au-Prince. The toxicology of chemicals of three heavy metal (chromium, lead, and nickel) and fluoride, substances detected in groundwater and tap water, has been reviewed. The information available on the effects of the selected heavy metals highlights major chemical risks, particularly for children, relating to Pb (II), Cr (III), Cr (VI) and Ni (II) contained in the groundwater were also characterized [27]. The level of pollution of underground water resources in the metropolitan area of Port-au-Prince does not only require the application of an approach based on water treatment processes. It also reflects the need to approach the issue of the quality of water intended for human consumption in this urban space based on a transdisciplinary approach based on the theories of medical geology and the approach. One Health. Indeed, the level of organic and mineral pollution of these resources can compromise the rare efforts made to achieve the SDGs, more particularly the 3, 6, 11, 13. The results available in the literature and used in the context of this work clearly indicate the existence of chronic toxicities of trace heavy metals (Cr, Pb, Ni), fluoride and hardness of drinking water on the human organism and on kidney tissues. In the future, it will be necessary to initiate research work on the combined effects of these substances from observations on laboratory animals and then proceed to modeling to finally arrive at an understanding of certain interactions that may exist between these pollutants.
Acknowledgments
The authors are thankful to the “One Health” University Space of Quisqueya University, FOKAL-Open Society Foundation Haiti, the Agence universitaire de la Francophonie (AUF), the Representation of the Institute for Research for Development (IRD) in Mexico, Cuba, and Haiti, the SCAC (Service for Cooperation and Cultural Action) of the French Embassy in Haiti, and the AOG (Association communautaire paysanne des Originaires de Grande Plaine) for their support in carrying out this work.
\n',keywords:"chemical pollutions, drinking water, environmental health, medical geology, One Health, Haiti",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/76752.pdf",chapterXML:"https://mts.intechopen.com/source/xml/76752.xml",downloadPdfUrl:"/chapter/pdf-download/76752",previewPdfUrl:"/chapter/pdf-preview/76752",totalDownloads:204,totalViews:0,totalCrossrefCites:0,dateSubmitted:"April 8th 2021",dateReviewed:"April 16th 2021",datePrePublished:"June 8th 2021",datePublished:"December 15th 2021",dateFinished:"May 13th 2021",readingETA:"0",abstract:"The geophysical environment of the Republic of Haiti is characterized by hydrological and biogeographical climatic phenomena, and a relief marked by its rugged appearance. Most of the territory is occupied by mountains formed of limestone. The differences in level are very marked. Fragmentation is another feature of the relief. These environmental imperfections juxtaposed with difficult socioeconomic conditions and anthropogenic actions raise questions about possible chemical metal pollution of the country’s water resources. Indeed, the predominance of limestone in the Haitian geology generate water hardness, and in the case where the magnesium concentration is less than 7 mg/l, this water may be the source of cardiovascular diseases. Studies carried out on several water points show a total hardness greater than 200 mg/l. In Port-au-Prince, concentrations of lead ranging from 40 μg/L to 90 μg/L and high Cr (III) risks were measured and estimated in groundwater and drinking water. Concentration of fluorine ranging from 0 to 2 mg/l were obtained from water resources. Concentration above 1.5 mg/l have been found from alluvial aquifers. Chronic public health risks, such as cardiovascular diseases, deterioration of the psychological development of children, irreversible functional and morphological renal changes, and dental fluorosis, strain Haiti’s water resources. Chemicals’ exposures seem to pose a threat to public health in Haiti, which need to be studied. The aim of this study is: (i) to analyze the contribution of geology and anthropogenic actions in the alteration of water quality, (ii) to review the toxicology of chemicals detected in water distributed in Port-au-Prince.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/76752",risUrl:"/chapter/ris/76752",signatures:"Alexandra Emmanuel and Evens Emmanuel",book:{id:"10349",type:"book",title:"Environmental Health",subtitle:null,fullTitle:"Environmental Health",slug:"environmental-health",publishedDate:"December 15th 2021",bookSignature:"Takemi Otsuki",coverURL:"https://cdn.intechopen.com/books/images_new/10349.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-721-1",printIsbn:"978-1-83968-720-4",pdfIsbn:"978-1-83968-722-8",isAvailableForWebshopOrdering:!0,editors:[{id:"34101",title:"Prof.",name:"Takemi",middleName:null,surname:"Otsuki",slug:"takemi-otsuki",fullName:"Takemi Otsuki"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"293512",title:"Dr.",name:"Evens",middleName:null,surname:"Emmanuel",fullName:"Evens Emmanuel",slug:"evens-emmanuel",email:"evens.emmanuel@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"334364",title:"Ph.D.",name:"Alexandra",middleName:null,surname:"Emmanuel",fullName:"Alexandra Emmanuel",slug:"alexandra-emmanuel",email:"alex.emmanuel1603@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Medical geology and environmental health in the geographical context of Port-au-Prince",level:"1"},{id:"sec_2_2",title:"2.1 Environmental health and assessment of health risks associated with chemical mixtures in drinking water",level:"2"},{id:"sec_3_2",title:"2.2 Medical geology and ONE HEALTH approach in health risks assessment of drinking water in Haiti",level:"2"},{id:"sec_5",title:"3. Chemistry and toxicology of selected pollutants detected in water distributed in Port-au-Prince",level:"1"},{id:"sec_5_2",title:"3.1 Presence of fluoride in drinking water and risk for human health",level:"2"},{id:"sec_6_2",title:"3.2 Water hardness and human health",level:"2"},{id:"sec_7_2",title:"3.3 Groundwater pollution by heavy metals and human health",level:"2"},{id:"sec_7_3",title:"3.3.1 Effects of chromium on human health",level:"3"},{id:"sec_8_3",title:"3.3.2 Effects of lead on human health",level:"3"},{id:"sec_9_3",title:"3.3.3 Effects of nickel on human health",level:"3"},{id:"sec_12",title:"4. Conclusion",level:"1"},{id:"sec_13",title:"Acknowledgments",level:"1"}],chapterReferences:[{id:"B1",body:'Kılıç, Z.(2020). The importance of water and conscious use of water. Int J Hydro. 4(5):239–241. DOI: 10.15406/ijh.2020.04.00250'},{id:"B2",body:'Calderon R. L. (2000). The epidemiology of chemical contaminants of drinking water. 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Global, regional, and national burden of cardiovascular diseases for 10 causes, 1990 to 2015. Journal of the American College of Cardiology, 70(1), 1–25. doi:10.1016/j.jacc.2017.04.052.'},{id:"B107",body:'Lookens, J., Tymejczyk, O., Rouzier, V., Smith, C., Preval, F., Joseph, I., McNairy, M. (2020). The Haiti cardiovascular disease cohort: study protocol for a population-based longitudinal cohort. BMC Public Health, 20(1), 1–11. doi:10.1186/s12889-020-09734-x'},{id:"B108",body:'Emmanuel, A., & Simon, Y. (2018). Environmental lead exposure and its impact on the health of children, pregnant women, and the general population in Haiti. Haïti Perspectives, 6(3):5–11.'},{id:"B109",body:'Emmanuel, E., Angerville, R., Joseph, O., & Perrodin, Y. (2007). Human health risk assessment of lead in drinking water: a case study from Port-au-Prince, Haiti. International journal of Environment and pollution, 31(3–4):280–291.'},{id:"B110",body:'Caussy, D., Gochfeld, M., Gurzau, E., Neagu, C., & Ruedel, H. (2003). Lessons from case studies of metals: investigating exposure, bioavailability, and risk. Ecotoxicology and environmental safety, 56(1):45–51. doi:10.1016/S0147-6513(03)00049-6'},{id:"B111",body:'El Nemr, A., Khaled, A., Abdelwahab, O., & El-Sikaily, A. (2008). Treatment of wastewater containing toxic chromium using new activated carbon developed from date palm seed. Journal of Hazardous Materials, 152(1), 263–275. doi: 10.1016/j.jhazmat.2007.06.091'},{id:"B112",body:'McGrath SP, Smith S. 1990. Chromium and nickel. In: Alloway BJ, editor. Heavy metals in soils. New York, USA): John Wiley & Sons, Inc. p 125–150.'},{id:"B113",body:'Cervantes, C., Campos-García, J., Devars, S., Gutiérrez-Corona, F., Loza-Tavera, H., Torres-Guzmán, J. C., & Moreno-Sánchez, R. (2001). Interactions of chromium with microorganisms and plants. 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(Chapter 27).'},{id:"B119",body:'Fertmann, R., Hentschel, S., Dengler, D., Janßen, U., & Lommel, A. (2004). Lead exposure by drinking water: an epidemiologial study in Hamburg, Germany. International journal of hygiene and environmental health, 207(3):235–244. doi:10.1078/1438-4639-00285'},{id:"B120",body:'INERIS (Institut National de l’Environnement Industriel et des Risques). Plomb et ses dérivés, in Fiche de données toxicologiques et environnementales des substances chimiques. Paris: INERIS; ERIS-DRC-01-25590-ETSC-Api/SD-N 00df257, 90 p.'},{id:"B121",body:'Ab Latif Wani, A. A., & Usmani, J. A. (2015). Lead toxicity: a review. Interdisciplinary toxicology, 8(2):55. DOI: 10.1515/intox-2015-0009'},{id:"B122",body:'Needleman, H. (2004). Lead poisoning. Annu. Rev. Med., 55:209–222. doi:10.1146/annurev.med.55.091902.103653'},{id:"B123",body:'Christensen, J. M. (1995). Human exposure to toxic metals: factors influencing interpretation of biomonitoring results. Science of the total environment, 166(1–3):89–135. doi:10.1016/0048-9697(95)04478-J'},{id:"B124",body:'Cleymaet, R., Collys, K., Retief, D. H., Michotte, Y., Slop, D., Taghon, E., Coomans, D. (1991). Relation between lead in surface tooth enamel, blood, and saliva from children residing in the vicinity of a non-ferrous metal plant in Belgium. Occupational and Environmental Medicine, 48(10):702–709. doi:10.1136/oem.48.10.702'},{id:"B125",body:'Watt, G. C. M., Britton, A., Gilmour, H. G., Moore, M. R., Murray, G. D., & Robertson, S. J. (2000). Public health implications of new guidelines for lead in drinking water: a case study in an area with historically high water lead levels. Food and Chemical Toxicology, 38, S73-S79. doi:10.1016/S0278-6915(99)00137-4'},{id:"B126",body:'Jarvis, P., & Fawell, J. (2021). Lead in drinking water–an ongoing public health concern? Current Opinion in Environmental Science & Health, 100239. doi:10.1016/j.coesh.2021.100239'},{id:"B127",body:'Daldrup, T., Haarhoff, K., & Szathmary, S. C. (1983). Fatal nickel sulfate poisoning. Beitrage zur gerichtlichen Medizin, 41, 141–144.'},{id:"B128",body:'Sunderman Jr, F. W., Hopfer, S. M., Sweeney, K. R., Marcus, A. H., Most, B. M., & Creason, J. (1989). Nickel absorption and kinetics in human volunteers. Proceedings of the Society for Experimental Biology and Medicine, 191(1), 5–11. doi:10.3181/00379727-191-42881'},{id:"B129",body:'Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological Profile for Nickel. Altanta, GA: U.S. Department of Health and Human Services; 1993. http://www.atsdr.cdc.gov.'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Alexandra Emmanuel",address:null,affiliation:'
Groupe Haïtien d’Études et de Recherche en Environnement et Santé (GHERES), Pétion-Ville, Haiti
Association Haïtienne Femmes, Science et Technologie, Haiti
Groupe Haïtien d’Études et de Recherche en Environnement et Santé (GHERES), Pétion-Ville, Haiti
Université Quisqueya, Laboratoire Santé-Environnement (LS-E), Port-au-Prince, Haiti
'}],corrections:null},book:{id:"10349",type:"book",title:"Environmental Health",subtitle:null,fullTitle:"Environmental Health",slug:"environmental-health",publishedDate:"December 15th 2021",bookSignature:"Takemi Otsuki",coverURL:"https://cdn.intechopen.com/books/images_new/10349.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-83968-721-1",printIsbn:"978-1-83968-720-4",pdfIsbn:"978-1-83968-722-8",isAvailableForWebshopOrdering:!0,editors:[{id:"34101",title:"Prof.",name:"Takemi",middleName:null,surname:"Otsuki",slug:"takemi-otsuki",fullName:"Takemi Otsuki"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"298118",title:"Dr.",name:"Tamara",middleName:null,surname:"Dzamonja Ignjatovic",email:"tamara.dzamonja@gmail.com",fullName:"Tamara Dzamonja Ignjatovic",slug:"tamara-dzamonja-ignjatovic",position:null,biography:"Tamara Dzamonja currently works at the Department of Psychology, University of Belgrade. Tamara does research in Personality Psychology, Clinical Psychology, and Abnormal Psychology. Their most recent publication is 'How services for children with disabilities in Serbia affect the quality of life of their families'.",institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"2",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:{name:"University of Belgrade",institutionURL:null,country:{name:"Serbia"}}},booksEdited:[],chaptersAuthored:[{id:"67452",title:"Services for Children with Disabilities and Their Families: The Impact on the Family’s Life Quality",slug:"services-for-children-with-disabilities-and-their-families-the-impact-on-the-family-s-life-quality",abstract:"Families that have children with disabilities are faced with numerous difficulties in Serbia mostly due to the prolonged effect of social and economic crises. Besides insufficient adequate and diverse community-based services, they often experience social isolation and poverty, too. During the last decades, there were efforts to improve support for parents by introducing community-based services for their children with disabilities. This chapter is based on the findings of the study that explored the effect of those services on the families’ quality of life. Although the findings confirmed that the services generally improved their life quality, particularly for those who perceived the lowest quality of life before, there are some additional observations about “side effects” that should be useful guidelines for developing flexible individually tailored service that support families’ needs and suit them best.",signatures:"Tamara Džamonja Ignjatović",authors:[{id:"298118",title:"Dr.",name:"Tamara",surname:"Dzamonja Ignjatovic",fullName:"Tamara Dzamonja Ignjatovic",slug:"tamara-dzamonja-ignjatovic",email:"tamara.dzamonja@gmail.com"}],book:{id:"7810",title:"Quality of Life",slug:"quality-of-life-biopsychosocial-perspectives",productType:{id:"1",title:"Edited Volume"}}},{id:"76897",title:"Main Concerns in Times of COVID-19 in Three Groups of People: Italians, Romanian Immigrants in Italy, and Romanians in Romania",slug:"main-concerns-in-times-of-covid-19-in-three-groups-of-people-italians-romanian-immigrants-in-italy-a",abstract:"This chapter is a description of results of a study conducted in Italy involving Italians (N = 491), Romanian immigrants (N = 275), and Romanians in Romania (N = 312) with aim to explore the principal sources of anxiety and uncertainty during COVID-19 pandemic, and the differences between the groups. In addition, the study analysed the role of resilience as a potential moderator between perception of sources of anxiety during COVID-19 and distress. A questionnaire was administered containing several scales. Results showed that Italians and immigrants have similar concerns and that the perception of resilience play significant role in determining emotional distress.",signatures:"Ankica Kosic and Tamara Dzamonja Ignjatovic",authors:[{id:"298118",title:"Dr.",name:"Tamara",surname:"Dzamonja Ignjatovic",fullName:"Tamara Dzamonja Ignjatovic",slug:"tamara-dzamonja-ignjatovic",email:"tamara.dzamonja@gmail.com"},{id:"349395",title:"Associate Prof.",name:"Ankica",surname:"Kosic",fullName:"Ankica Kosic",slug:"ankica-kosic",email:"anna.kosic@uniroma1.it"}],book:{id:"10814",title:"Anxiety, Uncertainty, and Resilience During the Pandemic Period",slug:"anxiety-uncertainty-and-resilience-during-the-pandemic-period-anthropological-and-psychological-perspectives",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"236474",title:"Prof.",name:"Pavol",surname:"Peráček",slug:"pavol-peracek",fullName:"Pavol Peráček",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"236479",title:"Prof.",name:"Janka",surname:"Peráčková",slug:"janka-perackova",fullName:"Janka Peráčková",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"258729",title:"M.D.",name:"Manuel",surname:"Cortés",slug:"manuel-cortes",fullName:"Manuel Cortés",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"291624",title:"Dr.",name:"Jorge",surname:"Rojas Hernández",slug:"jorge-rojas-hernandez",fullName:"Jorge Rojas Hernández",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:'Master in Sociology / Political Science, Dr. Phil. in Sociology, Leibniz Universität Hannover, Germany. Researcher at the Institute of Sociology of the Hannover University (1983-1993). Professor of the Department of Sociology and the Doctorate in Environmental Sciences, Universidad de Concepción. Dean of the Faculty of Social Sciences (2008-2013). Vice-rector for Institutional Relations and Relations with the Environment of the University of Concepcion (2015- May 2018). Director of the Department of Sociology. ANILLOS / CONICYT Project Director “Social and environmental impacts of global climate change in the Bío-Bío Region: Challenges for the sustainability of the 21st century”. Researcher at the Center for Water Resources for Agriculture and Mining (CRHIAM). Researcher of the project "Transnational change, social inequality, intercultural exchange, and aesthetic manifestations: Patagonia", Friedrich Schiller Universität Jena, Germany. Researcher of the Project "Emancipatory practices and transforming decolonizing methodologies", Latin American Council of Social Sciences (CLACSO). Co-editor of the book “Seguridad Hídrica. Water rights, scarcity, impacts and citizen perceptions in times of climate change ”. Editorial RIL, 2020. He has published more than 140 articles, books, and book chapters. Specialist in: social theory, globalization, regional development, work, citizen participation, environment, and global climate change.',institutionString:null,institution:{name:"Gottfried Wilhelm Leibniz Gesellschaft",institutionURL:null,country:{name:"Germany"}}},{id:"295508",title:"Ph.D.",name:"Pablo",surname:"Tomas-Carus",slug:"pablo-tomas-carus",fullName:"Pablo Tomas-Carus",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"297918",title:"M.D.",name:"César",surname:"Velasco",slug:"cesar-velasco",fullName:"César Velasco",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"304164",title:"MSc.",name:"Nilton",surname:"Leite",slug:"nilton-leite",fullName:"Nilton Leite",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"304166",title:"Prof.",name:"Armando",surname:"Raimundo",slug:"armando-raimundo",fullName:"Armando Raimundo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Évora",institutionURL:null,country:{name:"Portugal"}}},{id:"305413",title:"Ph.D. Student",name:"Javier",surname:"Lastra-Bravo",slug:"javier-lastra-bravo",fullName:"Javier Lastra-Bravo",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"306906",title:"Dr.",name:"Guillermo",surname:"Ortiz-Luna",slug:"guillermo-ortiz-luna",fullName:"Guillermo Ortiz-Luna",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null}]},generic:{page:{slug:"OA-publishing-fees",title:"Open Access Publishing Fees",intro:"
The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
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4,000 GBP Compacts Monograph - Short Form
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850 GBP Journal Article (Across Portfolio)
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Services included are:
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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If your manuscript:
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Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
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If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Choosing to publish with IntechOpen ensures the following benefits:
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,700 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
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Currently strongest OA platform with over 175 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
\n\n
The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
\n\n
OAPF Publishing Options
\n\n
\n\t
1,400 GBP Chapter - Edited Volume
\n\t
850 GBP Chapter - Book Series Topic (Annual Volume)
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10,000 GBP Monograph - Long Form
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4,000 GBP Compacts Monograph - Short Form
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850 GBP Journal Article (Across Portfolio)
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During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\n\n
Services included are:
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An online manuscript tracking system to facilitate your work
\n\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
\n\t
Assurance that your manuscript meets the highest publishing standards
\n\t
English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\n\t
Discoverability - electronic citation and linking via DOI
\n\t
Permanent and unrestricted online access to your work
\n
\n\n
What isn't covered by the Open Access Publishing Fee?
\n\n
If your manuscript:
\n\n
\n\t
Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
\n\t
Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
\n
\n\n
Benefits of Publishing with IntechOpen
\n\n
\n\t
Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+5,700 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes that assure your research is made available to the scientific community without delay
\n\t
Personal support during every step of the publication process
\n\t
+184,650 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 175 million downloads
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He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. 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He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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