ACUTE AND CHRONIC EFFECTS OF LEAD ON RESISTANCE VESSELS

Abstract

Objective: To present an updated narrative review of lead effects on resistance vessels. Method: This is a structured narrative review in three distinct phases: 1) preparation of the guiding question: “What are the acute and chronic effects of lead on resistance vessels”; 2) Sampling in the literature and selection of studies; 3) critical analysis of the selected studies. Results: we obtained a review of the history, characteristics, levels of lead and legislation, sources of exposure, use, kinetic and distribution of lead in the human body. In addition to the acute and chronics effects of lead on resistance vessels. Conclusion: studies show that the effects of lead contribute to cardiovascular changes being a risk factor for the population.

Heavy metals are considered ubiquitous in nature     contributing     to    environmental

contamination and consequently constitute a risk factor for human and animal health.¹ It is known that there are about twenty metals considered to be toxic to organisms, among them stand out lead, cadmium, copper and mercury. It is known that even in regions where contamination levels are not sufficient to cause acute poisoning, bioconcentration of these metals in the food chain, for an indeterminate period of time may cause damage to the detectable health.²

Lead is a toxic element naturally occurring widely used for thousands of years. This is one of the most common contaminants in the environment, due to the numerous industrial activities that favor its large distribution and are therefore one of the main contaminants of the environment.^3,4 Thus, all human beings have lead in their bodies as a result of exposure to exogenous sources.⁵ Despite this metal show no physiological function in the body, its toxic effects on humans and animals have been known for a long time for promoting changes in almost all organs and systems of these espécies.⁶

In general, lead affects all organics systems being able to change the hematological^3,7 and immunological systems.⁸ This event may occur from intrauterine life, contributing to the development of fetuses and infants with disorders in the immune system, which in adulthood may be more susceptible to allergic problems, infection, cancer or autoimmune disease.⁹

The toxic effects of the metal on the nervous tissue cause encephalopathies (children and adults) and changes in the peripheral nervous system, observed mainly in adults patients.^3,5,7,10 Several studies have shown that lead poisoning in children can produce permanent damage to the nervous system, including learning disabilities and reduced intelligence quotient (IQ);¹¹ behavioral problems^12-14 and commitment in memory.¹⁵ In addition, several studies have suggested that this metal reduces the physical growth and stature of children.^16,17

This cation affect the endocrine system coursing with change, for example, the hypothalamic-pituitary-thyroid axis and suprarenal gland.^5,7,18,19

The renal system is also a target for lead action, therefore, excessive and prolonged exposure to this metal can cause progressive and irreversible kidney disease, such as nephropathy lead, characterized by decreased renal function and most often it is accompanied by hypertension.^3,5,20

Moreover, this metal is classified by the “International Agency for Research on Cancer” (IARC) as a probable human carcinogen and the kidneys are the organs most susceptible to cancer development in rats exposed to lead. Added to this the fact are the cumulative mechanisms appearance of renal tumors in humans that are also relevant.^21,22

Regarding the cardiovascular system, there are many studies that report adverse effects of lead, one of the constituents involved as cause of hypertension.^23-26 In this sense, there are several studies that indicate that both occupational exposure and environmental exposure might promote increase in blood pressure.^27-29

According to data presented by the Ministry of Health (2006), in Brazil there are no reliable records on the number of individuals exposed occupational and environmentally to this metal. Although this is an important risk factor to human health, it is not yet well established actual by the toxicity of this metal in the human body. Moreover, there is no consensus among toxicovigilance agencies regarding the reference values and biological limits allowed for individuals exposed to this metal. Another worrying fact is the lack of information by the population, in general, on the main sources of exposure and the harmful effects of this metal to the health of individuals.

The main objective of this review is to describe scientific evidence in the literature related to the toxic concentration of lead in the human body and the impact on public health. In addition, it intends to describe the sources of exposure and use of lead by man; demonstrate the kinetics and distribution of this metal in the human body and describe the acute and chronic effects of lead on the cardiovascular system.

Method

This is a narrative review related to the effects of lead exposure on vascular function. We chose this type of review that enables the incorporation of evidence for convenience, by an expertise in the subject, in order to build a body of knowledge on a particular topic of scientific relevance.

The review process was systematized in three distinct phases, the first one on the elaboration of guiding question: “What are the acute and chronic effects of lead on resistance vessels?” The second phase corresponded to the sampling in the literature, which sought to include the broadest possible range of products identified and ensure the variety and magnitude of results.

Accordingly, an electronic check was performed on the LILACS (Latin American and Caribbean) and MEDLINE (National Library of Medicine, United States). The electronic search was performed using the following combinations of Health Sciences Descriptors (DeCS), “lead exposure; blood lead Concentrations; population exposure; effects of lead; vascular reactivity; resistances arteries; mesenteric artery”, and was based on the adoption of the following inclusion criteria: indexing studies in their databases in Portuguese, English and Spanish. They were defined as exclusion criteria: production without text available in full or central theme unrelated to the theme study.

The third phase of this review was the critical analysis of the selected studies. The decision of the inclusion or rejection of the studies was based on reading the titles of the selected studies, followed by critical analysis of abstracts, and studies with central topic not related to the proposed theme for review were rejected. In a second analysis, we proceeded to check contents in full, which was guided by the thematic analysis to identify the main ideas presented.

Result / Discussion

– Exposure to the metal as a public health problem: history, characteristics, levels of lead and legislation.

Lead was one of the first metals to be used by man, being known since 3500 B.C., according to archaeological discoveries made in Egypt. There are reports that the Egyptian civilization used lead in minting coins and manufacturing of cosmetics. During the Roman Empire this metal is widely used in the manufacture of pipes for the sewer system; weapons and household items such as cups, bowls and containers for liquids and food; plus aqueducts and tanks for fermentation and alcoholic beverage packaging.³⁰

Lead belongs to the chemical family metals of group IVb of the periodic table. Its atomic number is 82, its chemical symbol is Pb.³¹ It is a bluish-graymetal, shiny, odorless, malleable, insoluble in organic solvents and corrosion resistant. It is solid at room temperature, melts at 327 °C, vaporization temperature at 1725 °C. It is found in nature in either free form or in combination with various other metals. These properties determine its wide application in industry and commercial importance in the world market.^3,32,33

As lead is used for so long, the history of poisoning by this metal is also extensive. Hippocrates in the fifth century B.C., was the first to relate the lead intoxication symptoms to their causal factor.³⁴ Other occupational poisoning reports were pronounced in England in 1883 by workers who used the metal as raw material.³⁵ The lead poisoning cause one of the oldest occupational diseases, called Saturnism or Plumbism. The lead poisoning term is a reference to God Saturn, idolized in Ancient Rome. Thus, neurological effects of poisoning by the metal were first described in the Roman Empire.³⁵ Over the years, advances in experimental animals and fish models allow greater understanding of the toxic effects of lead in various body systems.

Currently, several studies suggest lead as a risk factor for the development                         of cardiovascular, neurological, gastrointestinal, hematologic, renal and other diseases. Therefore, this metal has been considered a serious problem for public health. However, it is still necessary to develop the area of ​​toxicology research not only to increase knowledge of the toxic effects, but also for the development of preventive measures and findings for possible treatments to be used in cases of poisoning by this metal.^4,35,36

Through various forms of metal exposure, especially occupational, and considering lead a problem for public health, few countries have established a maximum level of lead in the blood above which the person may be removed from work.³¹ In the decades of 60 and 70 common levels of maximum 100 µg/dL were found. Currently, these levels were reduced to the range of 40 to 60 µg/dL in different countries.³⁷

The Agency for Toxic Substances and Disease Registry (ATSDR)⁷ recommends be holding a blood concentration of lead below 30 µg/dL in adults. In occupational exposure environments levels of blood lead concentration should not exceed 60 µg/dL. Moreover, the American Pediatric Association (APA) considers levels of blood lead concentration ≥ 10 µg/dL excessive for children.

In Brazil, according to a regulatory rules 7 (NR7) of the Ministry of Labor (1988),³⁸ revised in 2013, the normal reference values, which is the value to be found in non-occupationally exposed population, the Biological Maximum Indexes permitted, are respectively 40 µg/dL and 60 µg/dL.^38,39 It is noteworthy thatthe NR-7 (No. 24 of 12/29/94), also determines the annual monitoring toxic effects of lead through medical examinations in exposed workers.

However, it is shown that lead levels in the blood, lower than the values fixed by these organs, can cause alterations in mood, in memory disorders, in verbal association, in visual intelligence and in attention to metal workers exposed, as well as cardiovascular disorders.^36,40

– Sources of exposure and use

Lead is relatively abundant in the earth’s crust, being the fifth most abundant metal on the planet.⁴¹ Their average concentration in the soil is 10 to 20 mg/kg. In the atmosphere, the concentration was estimated at about 0.0005 μg/m³ in the air and natural surface water the metal concentration is around 0.02 μg/L.³

The highest natural sources of lead are volcanic emissions, geochemical weathering and water mist, and the geological sources of lead arethe igneous and metamorphic rocks.^3,31 In addition to these lead sources, soil contamination can through man-made activities (anthropogenic), mainly from the recovery of metal scrap and waste.³¹ In Brazil, a secondary source of lead is obtained mainly from the recycling of automotive batteries, industrial and telecommunications.³⁹ The emission of gases and particulates resulting from the process of production and recycling are the major polluters of the environment. However, recycling is still the economically activity more feasible for the extraction.⁴¹

Because of the extensive use of metal, the man is the main target of exposure due to the contact with lead in their activities. Lead is used in over 200 different industrial processes. The alloys and compounds are used in the manufacture of high-tech products such as, protection of nuclear reactors, thin plates of electronic components, welding processes, as well as batteries, paints and dyes, ceramics, cables and ammunition.^42,43

Lead is used in the form of blades, pipes or cables, providing greater flexibility and corrosion resistance. It serves as a shield against ionizing radiation and is also used as protection in battery manufacturing.⁴²

Lead oxides are used in the plates of electric batteries and accumulators, as components in manufacturing rubber (PbO) as ingredients in inks (Pb₃O₄) and vitrified constituent, enamels and glasses. It is estimated that the battery manufacturing accounts for about 70% of world consumption of this metal.³

The presence of lead in paint was and is still used in the decoration of interiors and exteriors of homes as well as toys and furniture. Exposure to lead through the paint may occur during manufacturing and continue for many years with the deterioration or paint removal.⁴⁴ In Brazil, in August 2008 was published the Law No. 11,762, which regulates the use of pigments and driers based on lead in paints. The law states that paints cannot contain lead in concentrations equal to or greater than 0.06% by weight.⁴⁵

Lead arsenate is used in the manufacture of insecticide; lead carbonate is employed in the synthesis of polyvinyl chloride (PVC); lead acetate is important to use as varnish, antirust paintings, analytical reagent. This metal is also used in fertilizers or agricultural fertilizers, distributed into the environment.^30,31

The tetraethyl lead was used for a long time in Brazil (1922) in gasoline to increase the power of car engines and get better fuel economy.⁴⁶ But since 1978 was banned and in its place is used ethanol.³¹This fact has led to a drastic reduction of the contact with lead of the general population.⁴⁷ However, in many countries, there are still places where gasoline is a permanent source of exposure to this metal.

In developed countries, the control of lead pollution sources is being implemented gradually, with an intense action of environmental organizations and public health. In Brazil, control is virtually non-existent due to lack of data on the actual exposure of the population and interest of national supervisory bodies. Therefore, it is necessary studies that show the risks of exposure to greater understanding of our reality and thereby encourage the public health and the Environment authorities in the control actions.⁴

– Kinetics and distribution of lead in the human body

As described above, lead is a metal widely used for thousands of years. It is considered an environmental contaminant due to the numerous industrial activities that favor its distribution. Thus, all individuals have lead in their bodies as a result of exposure to exogenous sources. In order to correlate the amount of environmental lead and its bioavailability with its toxic effects on the body, it is important to understand the continuous interaction between the absorption, distribution, storage and disposal of this metal.⁴

– Absorption

The lead absorption process from environmental sources depends on the amount of metal, the physical and chemical state, in addition to being influenced by host factors (age, genetic, physiological state) and nutritional conditions.³¹ Most of lead enters the human body through the respiratory and gastrointestinal tract and only in its organic form, can enter the body through the skin.³⁴ the respiratory tract is the main lead absorption through occupational exposure.³¹

– Distribution

Some hypotheses regarding kinetics of lead distribution have been made decades ago by the scientific community. One of the main ideas based on the distribution model in three compartments: blood, soft tissue and mineralized tissues.^7,31 The half-life of this metal in the three compartments is quite different, being estimated at 36 days for the blood, 40 days for soft tissue and 27 years to the bone.³

The lead concentration in the blood is less than 2% of the total in the body. The metal present in the blood is distributed among the organs, mainly depending on the affinity for specific tissue. High levels have been found in aorta, liver and kidneys. The retention of lead stabilizes in the soft tissue in adult life and in some organs may decrease with age, but continues to accumulate in the bones and in the aorta throughout life.^5,34

In adults, approximately 95% of lead body load is in bone. Since this metal is an organic calcium analogue, its primary site of deposition is the bone tissue. Given the long half-life for lead in bone, this compartment serves as an endogenous source of metal for others compartments, long after exposure has ceased.^3,4 The mobilization of this cation to blood compartments, in pregnant women, it is of great importance and constitutes a risk to the fetus and mother.³

– Excretion

The excretion of lead in the human body is slow, with a half-life of about 10 years.³⁴ This metal is excreted by different routes among which include: renal (75-80%) and gastrointestinal (15%) excretion.There are other sources of excretion which together correspond to 8%, they are: sweat, skin peeling, hair, nails and breast milk.^31,48

– Acute and chronic effects of lead on resistance vessels

Resistance arteries are called as this for presenting a diameter smaller than 500 micrometers. They play a key role in the total vascular resistance and therefore in the maintenance of blood pressure homeostasis.⁴⁹ Peripheral vascular resistance is inversely proportional to the vessel radius to the fourth power and therefore reduction of the diameter of these arteries can produce significant increases in peripheral resistance and thereby the blood pressure.⁴⁹ In the literature, there are few reports associating the acute or chronic lead treatment to changes in vascular function of resistance arteries.

Studies showed an association between blood lead levels and hypertension in animals and humans.^50-53 Simoes et al.⁵⁴ demonstrated that low doses of lead are already strongly associated with the development of hypertension.

The etiology of the lead-induced hypertension is described to be caused by inhibition of Na, K-ATPase⁵⁵ by reducing the bioavailability of nitric oxide plus increased endothelial production of endothelin.^56-59 Furthermore, increased production and involvement of free radicals in the metal exposure reduces the bioavailability of NO⁶⁰ and depletes  the antioxidant reserves,^53,61 or in some cases, causes it to increase in an attempt to minimize the oxidative effects.⁶¹ The increase in ACE activity,^50,62 Cyclooxygenase-2,⁵⁴ the endothelial dysfunction⁵⁹ has also been reported as changes produced by lead.

In addition to these mechanisms, increased sympathetic nerve activity, reduced baroreflex sensitivity and reduced parasympathetic tone are involved in the lead-induced hypertension.^50,63,64

Vascular changes introduced by lead exposure are well described in conductance arteries such as the aorta. However, the effects of lead on resistance arteries need to be better defined, in low doses or large doses in acute or chronic exposure.

Skoczynska and colleagues⁶⁵ showed that in studies of infusion after norepinephrine administration, the vasoconstriction was more pronounced in mice treated with lead. Furthermore, they showed that small doses of lead enhance the response of alpha receptors and decreased the response of beta receptors in blood vessels.

Studies in animals and humans have demonstrated that exposure to low doses of lead produces hypertension and lead can cause contraction of vascular smooth muscle.^59,66 Watts et al,⁶⁷ showed that acute lead exposure in organ bath interacts with PKC in a calcium-dependent and endothelium-independent way to cause the contraction of vascular smooth muscle cells in mesenteric arteries of rabbits.

Recently, Covre et al,⁶⁸ evaluated the effects of exposure to low concentrations of lead in lung of mice resistance arteries and showed that the treatment for 7 days at low concentrations promoted an increase in lead deposition in the vascular bed and brought to increased production of superoxide anion in these arteries. Additionally, there was a reduction of vasoconstriction and endothelium-dependent vasodilation to acetylcholine was unchanged. This reduction in contraction was due to increased hyperpolarization by SKCa channels and Kv, probably as a compensatory mechanism for the decreased responsiveness to NO.

Studies Skoczyńska et al.⁶⁹ showed that the vascular effect of dopamine in rats intoxicated with lead and cadmium do not change compared with control. However, these metals modify the reactivity of the mesenteric vessels to angiotensin, and prostaglandins, by the pressor action of dopamine. The literature describes the effect of COX-2 derived prostanoids on vascular effects by lead exposure on the vascular reactivity of aorta.⁵⁹ It is also known that the presence of COX-2 in the muscle layer of the arteries contributes mainly to change the tone vascular⁷⁰ and the increased vascular COX-2 expression is often associated with hypertension.^71,72

Studies with resistance arteries should be priority. As we see in these few studies, this bed is directly affected by lead exposure and the mechanisms involved in these changes may contribute to explain the increase in blood pressure in animal models and exposed persons.

Final considerations

Lead is a heavy metal, widely distributed in nature and used by man. In view of the extensive documentation of the toxic effects of lead on the cardiovascular system, a more detailed elucidation of cellular targets and mechanisms through which lead exerts its effects must be performed because the metal exposure becomes a health risk with severe physiological consequences. Regarding the effects of lead on the resistance arteries, it is noteworthy that, although few studies have been shown that the metal causes impaired function of these vascular beds, both in acute and chronic exposure to lead. The actions of lead in resistance arteries potentiate the harmful effects of this metal on the cardiovascular system, promoting health risk as high blood pressure. Thus, it is necessary to evaluate the concentration levels established as safe for exposed and unexposed people, to reduce the deleterious effects of this metal for man.

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Authors

Maylla Ronacher Simões¹; Jonaína Fiorim²; Edna Aparecida Silveira³; Mirian Fioresi⁴

¹Doctor in Physiological Sciences by the Postgraduate Program in Physiological Sciences of the Federal University of Espírito Santo PPGCF-UFES; Post-doctoral student of PPGCF-UFES.

^2,3Doctors in Physiological Sciences at PPGCF-UFES; Physiotherapists in University Hospital Cassiano Antonio Moraes, HUCAM.

⁴Doctor in Physiological Sciences, at PPGCF-UFES; Professor in the Department of Nursing, UFES, Brazil.