Organ-Specific Effects and Toxicological Agents

**59**

**1. Introduction**

**Chapter 4**

**Abstract**

*and Isaac Omoche Odiba*

Review of Health Hazards

and Toxicological Effects of

*John Kanayochukwu Nduka, Henrietta Ijeoma Kelle*

**Keywords:** cosmetics, hazardous constituents, toxicological effects,

Body and personal care products (cosmetics) are designed to be applied on body parts for the purpose of enhancing cleaning, protecting, beautifying, healthy and young looking appearance or altering appearance without changing the body's operational nature [1, 2]. Body care products are of different kinds like skin moisturizers, perfumes, lipsticks and lip glosses, finger nail polishes, eye and facial makeup preparations, shampoo, hair colours and deodorant [3, 4]. A distinction that is made between cosmetics and drugs is that the latter is described as substances used as medicine or used in medicine. That is, drugs are intended to be used to treat or prevent ailments or diseases upon reaction with the human system. In addition, unlike cosmetics, drugs must be subjected to and pass premarket

public health issues, continuous cosmetic usage

Cosmetic products are designed for use on human body for beautifying and promoting attractiveness and appearance; for these reasons, cosmetics are in high demand especially among women of all ages in every country. Despite many vulnerabilities associated with cosmetic usage, the cosmetic and 'makeup' continues to enjoy wide acceptability irrespective of age and sex. This is made possible by massive advertising employed by producers and marketers of cosmetics. Advertising is the link between manufactured products and would-be consumers; it plays a crucial role in determining the product that is mostly patronised and vice versa. Therefore, ethical advertising that promotes utilitarian benefits of cosmetics should be encouraged over and above emotional advertisement that lowers self-esteem of consumers and offers such products as solution to their low self-esteem. Despite the ban in many countries of poisonous substances in cosmetic products, inexhaustive list of substances, such as lead, chromium, nickel, mercury, arsenic, cadmium, hydroquinone, steroids, nitrosamine, etc. are still present in many cosmetic products. In most cases, above regulatory values, cancers, renal disorders, thinning and easy brushing of the skin, dermatophyte infection with lesions, macular hyper pigmentation, pityriasis vesicular, diabetes mellitus, micropapular eruption, hypertension, etc. are possible toxicological and health hazards that may be associated with continuous cosmetic application.

Constituents of Cosmetics

#### **Chapter 4**

## Review of Health Hazards and Toxicological Effects of Constituents of Cosmetics

*John Kanayochukwu Nduka, Henrietta Ijeoma Kelle and Isaac Omoche Odiba* 

#### **Abstract**

 Cosmetic products are designed for use on human body for beautifying and promoting attractiveness and appearance; for these reasons, cosmetics are in high demand especially among women of all ages in every country. Despite many vulnerabilities associated with cosmetic usage, the cosmetic and 'makeup' continues to enjoy wide acceptability irrespective of age and sex. This is made possible by massive advertising employed by producers and marketers of cosmetics. Advertising is the link between manufactured products and would-be consumers; it plays a crucial role in determining the product that is mostly patronised and vice versa. Therefore, ethical advertising that promotes utilitarian benefits of cosmetics should be encouraged over and above emotional advertisement that lowers self-esteem of consumers and offers such products as solution to their low self-esteem. Despite the ban in many countries of poisonous substances in cosmetic products, inexhaustive list of substances, such as lead, chromium, nickel, mercury, arsenic, cadmium, hydroquinone, steroids, nitrosamine, etc. are still present in many cosmetic products. In most cases, above regulatory values, cancers, renal disorders, thinning and easy brushing of the skin, dermatophyte infection with lesions, macular hyper pigmentation, pityriasis vesicular, diabetes mellitus, micropapular eruption, hypertension, etc. are possible toxicological and health hazards that may be associated with continuous cosmetic application.

**Keywords:** cosmetics, hazardous constituents, toxicological effects, public health issues, continuous cosmetic usage

#### **1. Introduction**

Body and personal care products (cosmetics) are designed to be applied on body parts for the purpose of enhancing cleaning, protecting, beautifying, healthy and young looking appearance or altering appearance without changing the body's operational nature [1, 2]. Body care products are of different kinds like skin moisturizers, perfumes, lipsticks and lip glosses, finger nail polishes, eye and facial makeup preparations, shampoo, hair colours and deodorant [3, 4]. A distinction that is made between cosmetics and drugs is that the latter is described as substances used as medicine or used in medicine. That is, drugs are intended to be used to treat or prevent ailments or diseases upon reaction with the human system. In addition, unlike cosmetics, drugs must be subjected to and pass premarket

screening test(s) where they are proven to be safe and effective before they are marketed [3]. Certain chemicals that are part of cosmetic formulations have been found to be harmful, and the usage of cosmetic products containing such chemicals portends danger for human health. Inexhaustive list include heavy metals, hydroquinone, steroids, phenols and nitrosamines, etc. [1, 2, 5–9]. Surprisingly, in spite of the regulations put in place to prevent or minimize the presence of such ingredients in cosmetic brands, heavy metals, organic and inorganic chemical substances are still very much in them. A reason given for this is that such substances may be a major component of the raw materials used in cosmetic manufacture or are deliberately included in cosmetics [1, 6].

 Cosmetic products appear not to be subjected to clinical trials or laboratory testing(s) by regulatory authority in Nigeria before premarket approval. This is evident from legal document setting up the Nigerian National Agency for Food and Drug Administration and Control (NAFDAC). Guidelines stating the necessary requirement for registration of imported cosmetics in Nigeria are the attachment of certificate of analysis to the application for registration. This implies that safety and quality of products are monitored through post-market surveillance (PMS) activity. The implication is that laboratory/clinical testing of cosmetic products by NAFDAC takes place only when a victim of hazardous effect of cosmetic is reported or an end user discovers it to be defective or have side effects on the consumers. The guidelines prohibit mercury and its compounds, including corticosteroids. The reason is that mercury is a known cause of dermatitis and kidney damage which could manifest as hypertension. Continuous and possible excessive application of corticosteroids through cosmetics on the skin is reported to cause recalcitrant acne, red striae, excessive hairiness, proneness to infections, insulin related ailments and cataract [10]. Creams with hydroquinone at a concentration higher or in amount in excess of two percent (2%) are under prohibition because their side effect manifests as exogenous ochronosis which is depicted as a dirty brown pigmentation or colouration on areas of the body exposed to the sun followed by the skin's loss of elasticity [10].

 The cosmetic market in Nigeria is currently flooded with a variety of cosmetic products in response to the high demands for such products [7]. Nigeria with a conservative population estimated at 154,774,091 people as in February 2010 [11] whose citizens are regarded as being highly fashionable and glamorous provides an ever increasing market for cosmetic product manufacture, marketers and importers. Cosmetic manufacturers and marketers/distributors selling products containing mercury and corticosteroids usually violate fair packaging and labelling requirements by not always listing them as ingredients of the products. Furthermore, dark-skinned African populace use cosmetic majorly in an attempt to change their skin colour in response to social pressures [7]. Society tends to associate affluence (social and professional success) with physical attractiveness [12]. This may suggest the rationale behind the advertising strategy of most cosmetic manufacturers and marketers whereby their products are promoted majorly by exposing the populace to pictures of good-looking and even slightly above-average-looking females [3, 12]. It may also suggest the reason why Nigerian women were ranked high on a list of African countries known for patronizing skin lightening products [6].

Nigeria, irrespective of their social-economic background, attach a lot of importance to their looks and actively seek to improve such regardless of the cost or implications [7].

Although skin lightening products alter the body's structure and function by inhibiting and/or reducing melanogenesis [2, 6, 9, 13], they are classified as cosmetics rather than drugs and can be readily purchased over the counter at roadside non-pharmaceutical stores. As a result, these products are much more readily available, and since some of them come very cheap, anybody, regardless of *Review of Health Hazards and Toxicological Effects of Constituents of Cosmetics DOI: http://dx.doi.org/10.5772/intechopen.84590* 

socio-economic background would always find a product that is affordable [7]. The choice of product usage is compounded by ignorance, illiteracy and make-believe lifestyle. According to the Nigeria's National Literacy Survey [11] carried out by Nigeria's National Bureau of Statistics, the study revealed that the adult literacy level rate in English language stands at 57.9%. This makes it difficult for a large segment of the population (42.1%) to even read and comprehend the inscriptions on the label of cosmetic product, leaving them ignorant of the actual benefits and risks associated with the cosmetics they have decided to use. That aside, the quest for survival makes even the literate populace to pay little attention to information on content and instruction on direction of use that are contained on the product labels. A huge chunk of the cosmetic brands found in Nigeria are imported from America, Europe and Asia. It is not surprising, as Nigerians view products tagged 'foreign' as being of superior quality and therefore attach greater value to such products than locally manufactured ones. In order to maintain a clean and healthy environment that is free of pollution as well as protects public health, potential public health and environmental pollutant such as cosmetics must have their contents carefully and properly scrutinized and continuously monitored. The aim of this review is to X-ray the toxicological profile and effects of toxicants contained in cosmetic brands in Nigerian market and elsewhere.

#### **2. Types of cosmetics**

Many cosmetic products exist in Nigerian market and elsewhere across the globe; some are locally made, while others are imported. They may occur in liquid, semi-liquid, solid, granular and volatile form; examples include skincare creams, hair creams, toothpaste, soaps, perfumes, lipsticks, fingernail and the toe polish, eye and facial makeup, towelettes, permanent waves, hair colours, hair sprays and gels, deodorants, hand sanitizer, etc. [3]. A 'make-up is a micro aspect of cosmetics', which ordinarily can refer to colouring products intended to improve the user's appearance.

#### **3. Harmful substances in cosmetics**

The presence of some substances in cosmetics constitutes imminent danger to the users. Such substances that may cause damage to the users of cosmetics include but not only:

#### **3.1 Inorganic-heavy metals**

These are metals having a specific gravity greater than four (4). Sulphides of such metals are insoluble in water. Examples of heavy metals are cadmium, lead, nickel, mercury, manganese, chromium, thallium, etc. [14].

#### **3.2 Arsenic (As)**

 Arsenic occurs in many minerals, in conjunction with sulphur and other metals, and also as a pure elemental crystal. Arsenic is a metalloid. It can exist in various allotropes, although only the grey form has important use in industry [15]. It is notoriously poisonous to multicellular life, although a few species of bacteria are able to use arsenic compounds as respiratory metabolites. Arsenic contamination of groundwater is a problem that affects millions of people across the globe [16].

#### **3.3 Cadmium (Cd)**

 Cadmium belongs to group IIB (group 12) of the periodic table and is used in nickel-cadmium storage battery where it enhances long service life and a wide operating range. It occurs in nature mostly in zinc deposits in the mineral greenockite (CdS) and otavite (CdCO3). Its abundance in the earth's crust is estimated to be 0.15 mg/kg and in sea water 0.11 μg/L [17].

#### **3.4 Lead (Pb)**

Lead belongs to group IVA (group 14) of the periodic table. It is one of the oldest metals known to civilization. It is rarely found in nature in its native form but can be found in several minerals such as galena (PbS), angelsite (PbSO4) and cerussite (PbCO3). Its concentration in the earth's crust is 12.5 mg/kg and in sea water, 0.03 mg/L [17]. Lead and its alloys such as solder can be used in the construction of pipelines, plumbing fixtures, wires, ammunition, containers for corrosive acids and shield against short wavelength radiation.

#### **3.5 Nickel (Ni)**

Nickel is a transition metal, the most common oxidation state is +2, abundance in the earth crust is 84 μg/kg, and its average concentration in seawater is 0.56 μg/ mL. It occurs in nature as in pentlandite (NiFe)9S16, limonite (FeNi)O(OH).nH2O and garnierite (NiMg)6Si4O10(OH)8 [17]. Nickel metal is used in numerous alloys that are used to construct various equipment such as reaction vessels, plumbing parts, missiles and aerospace components. It is also used in catalysis [15].

#### **3.6 Chromium (Cr)**

Chromium belongs to group VIB (group 6) in the periodic table as a transition metal [15]. Chromium occurs in the mineral chromite, (FeO.Cr2O3), and its abundance in the earth's crust is estimated to be near 0.01%, and its concentration in sea water is 0.3 μg/L [17]. Its most important application is in the production of nickel-based alloys. Trace amounts of Cr are necessary in the diet of mammals. Cr3+ and insulin are both involved in maintaining the correct level of glucose in the blood. In cases of Cr deficiency, glucose is only removed from the blood half as fast as normal. Some cases of diabetes may reflect faulty metabolism of Cr [15].

#### **3.7 Manganese (Mn)**

 Manganese is distributed widely in nature, mostly as oxide, silicate and carbonate ores. It is the 12th most abundant element in the earth's crust. Its earth crust concentration is estimated to be 0.093%; average concentration in sea water is 2 μg/L. Most important industrial use is in ferrous metallurgy yet an essential element for plants and animals [17].

#### **3.8 Mercury (Hg)**

Mercury is the only liquid metal at standard temperature and pressure (STP), with a freezing point of −38.83°C and boiling point of 356.73°C; mercury has one of the narrowest ranges of its liquid state of any metal [18–20]. Mercury poisoning results from exposure to water-soluble forms of mercury (such as mercuric chloride or methylmercury), inhalation of mercury vapour, or eating seafood contaminated with mercury [15].

It is used in the manufacture of industrial chemicals, in electrical and electronic applications and in thermometers, especially when high temperatures are required. Larger proportions of gaseous mercury are used in fluorescent lamps, but its other applications are gradually replaced considering health and safety implications and in some applications totally substituted with less toxic but highly expensive Galinstan alloy [21].

 Compounds of mercury have found extensive application in medicine but are much less utilized nowadays than previously intended, since its toxic effects are more widely understood. The element mercury is an ingredient in dental amalgams. Thiomersal (called Thimerosal in the United States) is an organic compound used as a preservative in vaccines, though it has declined remarkably [22]. Another mercury compound merbromin (mercurochrome) is a topical antiseptic used for minor cuts and scrapes and is still in use in some countries. In the 1930s, some vaccines were preserved with thiomersal, which can convert to ethyl mercury on degradation or metabolism. Although it was generally speculated that this mercury-based compound (preservative) can cause autism in children, scientific proof to support the speculation was lacking (Parker et al., 2004). But as a precautionary measure, the US government has removed or drastically reduced thiomersal in all US vaccines recommended for children 6 years of age or below, with the exception of inactivated influenza vaccine [22].

Cinnabar, a mercury compound, was utilized in traditional Chinese medicines. When its safety considerations were reviewed, it was found that it can cause serious mercury intoxication on application of heat, taken in more required concentration or on continuous exposure time, and can have adverse effects at therapeutic doses, though this is typically reversible at therapeutic doses. Despite the fact that mercury in this form may be less toxic than others, its utilization in traditional Chinese medicine can be justified as the therapeutic basis for the use has not been proved [23]. Presently, its application in medicine has slowed greatly in all aspect, especially in developed countries. Some over-the-counter drugs such as topical antiseptics, stimulants, laxatives, diaper-rash ointment and eye drops contain mercury compounds. The FDA has inadequate data to establish general recognition of the safety and effectiveness of the mercury ingredients in these products [22].

Thiomersal is widely used in the manufacture of mascara. In 2008, Minnesota in the United States became the first state to ban intentional use of mercury in cosmetics [24]. A study of mean concentration of mercury in urine samples shows skincare products as a major exposure route to inorganic mercury among New York City residents. Population-based bio-monitoring confirms sea food and fish meals as a major source of mercury [25]. Mercury can be absorbed through the skin and mucous membranes, while the vapours can be inhaled, so containers of mercury are securely sealed to avoid spills and evaporation. Literature has shown that the most toxic forms of mercury are its organic compounds, such as dimethylmercury and methylmercury. Inorganic compounds are highly toxic by ingestion or inhalation [26].

#### **3.9 Nitrosamines**

 Nitrosamines are compounds of the chemical structure R1N (▬R2)▬N〓O, most of which are carcinogenic. They are formed when secondary amines react with nitrous acid (generated by action of dilute acid on nitrites) in an environment with pH values below 7 [27]. They are used in the manufacture of some cosmetics, in pesticides and in most rubber products. In 1956, two British scientists, John Barnes and Peter Magee, reported that dimethylnitrosamine produced liver tumours in rats. Research was undertaken, and approximately 90% of nitrosamine compounds were deemed to be carcinogenic [28]. In the 1970s, increased frequency of liver cancer was found in Norwegian farm animals that were fed on herring meal that

was preserved using sodium nitrite. The sodium nitrite had interacted with dimethylamine in the fish and produced dimethylnitrosamine [28].

#### **3.10 Nitrite**

 Nitrite is the univalent radical NO2 <sup>−</sup> with a molecular weight of 46 g/mol or a compound containing it, such as a salt or an ester of nitrous acid [29]. The nitrite ion NO2 <sup>−</sup> has a V-shape that is based on a plane triangular structure; with nitrogen [N] at the centre, two corners are occupied by oxygen [O] atoms, and the third corner occupied by a lone pair. As a result, the N atom is sp2 hybridized [15]. Nitrite is a weak oxidizing agent that oxidizes Fe2+ to Fe3+ and I<sup>−</sup> to I2, while it is reduced to N2O or NO.

#### **4. Organic substances**

#### **4.1 Hydroquinone**

Hydroquinone, known as benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol. Its chemical structure features two hydroxyl groups bonded to a benzene ring in a para position. In a substituted form, the derivatives of the compound can still be referred to as hydroquinone.

Since it is weakly acidic, the reactivity of O▬H groups of these compounds compares well with other phenols. Its conjugate base can easily undergo O-alkylation as to produce mono- and diethers. In the same way, hydroquinone is highly susceptible to ring substitution by Friedel-Crafts reactions such as alkylation. This reaction is used to produce much known antioxidants such as 2-tert-butyl-4-methoxyphenol ('BHA'). A very important dye quinizarin is produced by diacylation reaction of hydroquinone with phthalic anhydride [30], but the most important reaction is the conversion of hydroquinone to produce mono- and diamino derivatives—methylaminophenol, used in photography.

$$\text{C}\_6\text{H}\_4\text{ (OH)}\_2 + \text{CH}\_3\text{NH}\_2 \rightarrow \text{C}\_6\text{H}\_4\text{ (OH) (N (H) CHB)} + \text{H}\_2\text{O} \tag{1}$$

Also diamines, useful in the rubber industry as antiozone agents, can be produced from aniline:

$$\text{C}\_6\text{H}\_4\text{ (OH)}\_2 + 2\text{C}\_6\text{H}\_5\text{NH}\_2 \rightarrow \text{C}\_6\text{H}\_4\text{ (N (H) C}\_6\text{H}\_5\text{)}\_2 + 2\text{ H}\_2\text{O}\tag{2}$$

 The compound is variously used, mainly with its action as a reducing agent that dissolves in water. It is widely used in most photographic development for film and paper. It can act as an inhibitor by preventing polymerization of acrylic acid, methyl methacrylate, cyanoacrylate and other monomers that can respond to free radicalinitiated joining. This reaction utilizes the antioxidant properties of hydroquinone to undergo mild oxidation and convert to the compound parabenzoquinone, C6H4O2, often called p-quinone or quinone. This reaction is reversible as reduction

of quinone reverses this reaction back to the original form. Some biochemical compounds in nature have this sort of hydroquinone or quinone section in their structures, such as coenzyme Q, and can undergo similar redox interconversions. Hydroquinone can lose an H+ from both hydroxyl groups to form a diphenolate ion.

#### **4.2 Steroids**

This is an organic compound in which four cycloalkane rings are joined with each other; dietary fat cholesterol, the sex hormone—estradiol, testosterone and the anti-inflammatory drug dexamethasone are common examples. The steroid centre consists of 20 carbon atoms which are bound together where they exhibit the structure of 4 fused rings composed of 3 cyclohexane rings and 1 cyclopentane ring. They vary by the functional groups attached to this four-ring core and by the oxidation state of the rings [31]. All steroids are made in cells either from the sterol lanosterol (animals and fungi) or from cycloartenol (plants). Both lanosterol and cycloartenol are derived from the cyclization of the triterpene squalene [32].

Corticosteroids are a class of chemicals that includes steroid hormones naturally produced in the adrenal cortex of vertebrates and are involved in a wide range of physiological processes, including stress and immune response, and regulation of inflammation, carbohydrate metabolism and catabolism of protein. Synthetic glucocorticoids are used in the treatment of joint pain or inflammation, temporal arthritis, dermatitis, allergic reactions, asthma, hepatitis, systemic lupus erythematosus, ulcerative colitis, Crohn's disease and sarcoidosis and for glucocorticoid replacement or other forms of adrenal insufficiency (Higashi et al., 2009).

#### **5. Bibliographies that prove cosmetic brands are in continuous use and contain poisonous toxicants**

 An epidemiological survey was conducted by Adebajo [7] on the use of skin lightening cosmetics among traders in Lagos, Nigeria, using 450 traders from three major and popular markets (Tejuosho, Balogun and Mushin) in Lagos metropolis between May and July 1998 using stratified sampling method. Information on their socio-demographic characteristics, knowledge and attitudes to and the patterns of use of skin lightening cosmetics were elicited from the respondents with the application of questionnaire-based interview. The result obtained showed that for sociodemographic characteristics of the respondents that participated, 28.9% were males and 71.1% females. 51.6% were aged between 20 and 29 years with a mean of 30.8 years and about 49.3% were married. Over 95% of the respondents had some form of formal education with 31.1% who had at least primary school education and 119 postsecondary school education. Most of them (82.2%) were traders, while the remaining operated small-scale business such as hairdressing, barbing, tailoring and chemist. Many of them (45.6%) earned less than N1, 000.00, while 18 (4.0%) earned above N5, 000.00 per month. For patterns of use of skin lightening cosmetics, 348 respondents (77.3%) made up of 96 male traders (27.6%) and 252 female traders (72.4%) admitted using skin lightening cosmetics. Sex did not have any effect on the pattern of use of these cosmetics (p > 0.05). Hydroquinone-based cosmetics were the most widely used by the respondents, and the least use was the mercury-based ones; female traders generally tended to use more corticosteroid-based cosmetics much more than male traders. The modal duration of the use of the skin lightening cosmetics was 1–3 years, although 29 respondents (8.3%) had used them for less than 6 months and 44 (12.6%) for 5 years. Many of the respondents (45.7%) who admitted using the cosmetics spent between N250 and N500 per month on the cosmetics, while some

 (12.4%) spent between N500 and N1000. Over half of the respondent claimed that they discovered the skin lightening cosmetics themselves, while, 123 (35.3%) were influenced by their friends. Other sources of influence include health workers (2.3%), chemist (5.5%), parents (1.4%) and the media (1.4%). One hundred and nine respondents (31.3%) commenced the use of skin lightening cosmetics to treat skin blemishes. Almost one-third of the respondents (30.2%) indulged in the use of these cosmetics because they felt that being fair complexioned made them more attractive. Others use them to cleanse or tone their faces and bodies (21.0%), and the rest used them simply because they felt it was trendy to be fair complexioned. Only 14 respondents indulged in the use of skin lightening cosmetics to satisfy the desires of the opposite sex. Although the level of the use of skin lightening cosmetics increased with the level of education of the respondent, this was weakly significant (p = 0.05). One hundred and sixty seven (73.2%) Christians compared with 181 (81.5%) Moslems used bleaching creams. This difference was statistically significant (p < 0.05). On how respondents felt about their new look, most of the respondents (64.1%) felt they were more attractive; hence, they were more confident about their new look. Only 46 (13.2%) claimed they were relieved of their skin blemishes, while 33 (9.5%) were better appreciated by their spouses. About 50% of 348 respondents (made up of 44 males and 130 females) who use skin lightening cosmetics developed side effects. Respondents were more likely to develop side effects as duration of use increased from 6 months to 3 years. Beyond 3 years, however, fewer respondents developed side effects. The respondents reported several side effects, the commonest being yellowish brown colouration of the skin (23.9%). Others were skin rashes, multiple stretch marks, thinning and easy brushing of the skin. Twenty-five of the participants had worsening of their existing skin conditions, and on observing some of the side effects, 79 respondents (45.4%) just simply ignored the side effects, while only 35.6% stopped using the cosmetics. To mitigate against these problems, clinical trials should be conducted to ascertain the safety levels acceptable for the Nigerian skin types and climate.

Nnorom et al. [8] analysed the content of trace metal of several cosmetics in Nigeria for the presence of lead, cadmium, zinc and iron; three groups of facial cosmetics were used, such as eye pencil, eye liners and mascara, lipstick and lip gloss and native eyeliner (tiro and uhie) which were purchased from retail outlet and open market in Umuahia, Southeast Nigeria. The result from this study showed that the range of Pb levels for lipsticks is higher in concentration than that for local eyeliners, with the geometric mean value for the local eyeliners being 120.5 μg/g. Comparative amounts of Pb were found in the local eyeliners and pencil. Cd was generally low, being much less than 3 μg/g, while chromium was much higher than the corresponding levels of nickel and cadmium in each sample group. Cr, Fe and Zn were much higher in the samples than those of the non-essential metals, Pb, Ni and Cd. Zinc and Fe were in the highest concentration. The research concluded that the continuous use of these cosmetics could result in an increase in the trace metal levels in human body beyond acceptable limits.

 Nnoruka and Okoye [9] studied topical steroid abuse to document the prevalence, motives and observed complications of steroid use as depigmenting agent among African Blacks of Southeast Nigeria; consecutively new patients are attending the dermatological clinic of the University of Nigeria Teaching Hospital, Enugu. Nigeria, from June to December 2004, was recruited. All the participants were adults (males and females) and were recruited only if they use depigmenting agents. These was ascertained by obtaining information from the back of the containers or packets of waste containers; leaflets containing useful information concerning active ingredients were used to ascertain that the products contained well-known active lightening substances such as hydroquinone, mercury compounds and steroids. Questionnaire was used to obtain information on the most frequently

#### *Review of Health Hazards and Toxicological Effects of Constituents of Cosmetics DOI: http://dx.doi.org/10.5772/intechopen.84590*

used cosmetic and mode of application with full consent of the patients. Relevant information such as age, sex, occupation, demographic information as well as names and types of products utilized within the last three months; length of and regularity of application and body parts involved; amount or volume utilized monthly and cost involved were determined. Also medical history of the patients, if they have had other medical conditions such as hypertension, diabetes mellitus or renal disorders, and the duration of such problems. Manner and method of presenting the problem and clinical examination already are carried out in the affected areas. Where adequate information were not obtained or unsatisfactory, relevant laboratory tests like mycological studies, venereal disease research laboratory (VDRL), blood urea electrolytes, creatinine, urinalysis or skin biopsy were performed on the patients.

 The results they obtained showed that there were 547 (58.7%) patients utilizing depigmenting agents who met the criteria for the study, out of the 931 consecutive new patients recruited for the study. Of these, 414 (75.7%) were females and 133 (24.3%) were males within age range of 18–71 years. Traders (22.7%) accounted for the most affected, followed by businessmen and women. The duration of such practice varied from 3 months to 30 years. Utilization of topical steroid amounted to 57.2% (313) patients for depigmenting cosmetic agents. 5.9% (32) of participants agreed they were utilizing them as medication for various skin or surface body conditions such as eczema, papulosquamous disorders, sycosis barbae and connective tissue disorders. More than 21 different steroid-containing products were utilized, mostly class 1 steroid in 89.6% cases. These products include Topifram®, Topicort®, Topgel®, Topsyn®, Movate®, Dermovate®, Diprosone®, Visible Difference®, Betadine®, Bio Claire®, Betnovate–N, Neomedol®, Synalar®, Locacorten®, Palmer's Spot Remover®, Top Clear Skin®, Betnovate–C®, Neutone®, etc. Skin disorders documented during dermatologic/systemic examination included widespread dermatophyte infections with lesions, and diagnosis was frequently delayed or missed (tinea incognito). The distribution among the participants were, on the body in 191 (34.9%), macular hyper pigmentation of the face accounted for 204 (37.3%) cases, and these caused observable inflamed pustules and micropapular eruption masking the entire face. Pityriasis versicolor was very noticeable and situated at unusual sites, like the medial aspect of the upper and lower limbs among 31 (5.7%) patients. They had deep depigmentation and are linked with superficial atrophy; three patients among them had been associated with diabetes mellitus which is in early stage. Other disorders and complications observed were widespread striae in 161 (28.3%) cases, telangiectasia in 117 (21.3%), easy bruisability in 95 (17.4%) and hypertrichosis in 73 (13.3%) cases. The study concluded that cosmetic use of topical steroids exposes the users to several cutaneous complications alongside medical and aesthetic problems.

Amit et al. [33] determined lead and cadmium in cosmetic products, like soap, face cream, shampoo and shaving creams, using atomic absorption spectrophotometer. In samples consisting of a total of three different brands (coded A–C) of each product and total five samples of one brand of each sample collected from various retail shops from local market of Gwalior, India, the highest concentration of lead was detected in soap with brand code B (1.59 mg g<sup>−</sup><sup>1</sup> ), while face cream, brand code C (0.07 mg g<sup>−</sup><sup>1</sup> ) and talcum powder and brand codes B and C (0.24 and 0.25 mg g<sup>−</sup><sup>1</sup> ) showed lowest lead content. For comparison between same products with different brands, mostly brand A showed the highest concentration (soap, 4.63 mg g<sup>−</sup><sup>1</sup> ; face cream, 0.03 mg g<sup>−</sup><sup>1</sup> ; shampoo, 1.49 mg g<sup>−</sup><sup>1</sup> ; shaving cream, 0.69 mg g<sup>−</sup><sup>1</sup> ; and talcum powder, 0.38 mg g<sup>−</sup><sup>1</sup> ) followed by brand B (soap, 4; face cream, 0.05; shampoo, 1.59 mg g<sup>−</sup><sup>1</sup> ; shaving cream, 0.66 mg g<sup>−</sup><sup>1</sup> ; and talcum powder, 0.25 mg g<sup>−</sup><sup>1</sup> ). The highest concentration of cadmium was detected in

shampoo with brand code A (0.042 mg g<sup>−</sup><sup>1</sup> ) followed by soap with A and B brand (0.04 and 0.037 mg g<sup>−</sup><sup>1</sup> ). The findings showed that lead is a major toxic heavy metal in cosmetic products.

Oyelakin et al. [34] assessed the level of mercury in soaps by the use of cold vapour fluorescence spectrophotometric analysis in Gambia; a total of 16 brands of soaps were analysed. These brands of soap were grouped under four categories: medicated, toilet, skin lightening and laundry soaps. The soaps, purchased from different supermarkets in the Gambia, were used for analyses. They showed that all 16 soap brands contained mercury with concentration ranging from 2.87ng/g to 12.61 ng/g.

The World Health Organization [6] review on mercury in skin lightening products revealed that mercury is a common ingredient found in skin lightening soaps and creams as well as other cosmetics such as eye makeup, cleaning products and mascara. It stated that skin lightening soaps and creams are more commonly used in certain Africa and Asian nations and also among dark-skinned populations in Europe and North America. It further stated that mercury salts inhibit the formation of melanin, resulting in lighter skin tone. The review showed countries of greatest cosmetic use in Africa, Mali, Senegal, South Africa, Togo and Nigeria in order of increasing usage by women as 25, 27, 35, 59 and 77% are reported to use skin lightening products on a regular basis. Close to 40% of women surveyed in China, Malaysia, the Philippines and Republic of Korea in the year 2004 were reported to have used skin lighteners, while in India, 61% of the dermatological market were made of skin lightening products. The result also showed that skin lightening products are manufactured in many countries such as the Dominican Republic, Lebanon, Mexico, Pakistan, the Philippines, Thailand and the United States, and mercury-containing skin lightening products are available for sale over the internet, while individuals from Brazil, Kyrgzstan, Mexico, and the Russian Federation believe that mercury-containing skin lightening products are easy to obtain. Furthermore, the result revealed that skin lightening products come in different forms, including soap and creams, with the soap containing approximately 1–3% mercury iodide, and the cream is composed of 1–10% mercury ammonium (some soap products tested contained mercury at concentrations of up to 31 mg/kg, whereas cream products had mercury at concentration as high as 33,000 mg/kg).

 Oyedeji et al. [2] ascertained hydroquinone, chromium and aluminium levels in cosmetics are marketed in Nigeria with the aim of proving that they contained poisonous substances at levels harmful to the populace; 80 cosmetic emulsions were purchased from a wholesale supermarket in Ibadan, Southwest Nigeria. The various cosmetic emulsions country of manufacture were determined by inspection of labels on the cosmetic packaging. The concentration of hydroquinone (HQ ) was determined using a UV spectrophotometer. Heavy metals in the emulsion were determined by atomic absorption spectrophotometer. The study concluded that most of the cosmetic emulsion did not contain hydroquinone at levels that are detrimental to the skin, while the heavy metals were within acceptable values.

 Nduka et al. [35, 36] assessed the cancer and no cancer risk of heavy metals, steroids, hydroquinone, nitrosamines and nitrites in 42 cosmetic brands purchased from cosmetic shops in Southeastern Nigeria through dermal exposure pathway; the total cancer risk value for both the cosmetic products manufactured in Nigeria and the cosmetic products manufactured outside Nigeria was less than the regulatory purpose acceptable or tolerable risk level of 10<sup>−</sup><sup>6</sup> to 10<sup>−</sup><sup>4</sup> set by USEPA [37]. This implies that the low levels of these carcinogenic elements to which users of these cosmetics are continually exposed to through the dermal exposure pathway alone over their lifetime are unlikely to pose a non-cancer and cancer risk. This therefore confers a measure of safety and no toxicological concern, but the values for total cancer risk and non-cancer risk subsist entirely on the risk contributed

by the heavy metals and do not contain any risk that may be contributed by other hazardous substances as well as from other more common exposure pathways such as inhalation and ingestion.

#### **6. Toxicological effect of harmful substances in cosmetics**

Minimal exposure level to arsenic can lead to serious illness or death [38]. Result from Chile establishes a dose-dependent relation between chronic arsenic exposure and various forms of cancer, especially when other risk factors, such as cigarette smoking, are joined. The effect is established to persist below 50 ppb of arsenic [39]. Studies on inorganic arsenic exposure suggest a small but measurable risk increase for bladder cancer at 10 ppb [40]. The acute poisoning effects of cadmium are nausea, vomiting, diarrhoea, headache and shock; inhalation of its dust and fumes can cause cough, respiratory distress, congestion of lungs and bronchopneumonia [41]. The metal accumulates in the liver and kidneys, damaging these organs when the exposure is chronic. Biological half-life of cadmium in humans is estimated at 20–30 years. Cadmium is listed by the United States Environmental Protection Agency [42] as one of the priority pollutant metal [43]. Absorption of lead into the skin is governed by chemical structure; therefore, skin organic lead absorption into the body tissues is more rapid than with inorganic lead compounds because of greater lipid solubility; large amounts of lead gain access to nerve tissue [44]. Acute effects of lead intake are ataxia, headache, vomiting, stupor, hallucination, tremors and convulsions. Chronic cases include weight loss, anaemia, kidney damage and memory loss. Lead bioaccumulates in bones and teeth, and it is classified as an environmental priority pollutant by the US EPA. The safe level for drinking water is 15 μg/L [41].

Skin contact with nickel can cause dermatitis, and a type of chronic eczema known as 'nickel itch' is caused by hypersensitivity reactions of nickel on the skin [45]. Oral toxicity of nickel is very low, but ingestion results to hyperglycerine and depression of the central nervous system. Large dose inhalation of nickel dust can cause lung and sinus cancer in humans. Nickel and certain of its compounds are listed by International Agency for Research on Cancer (IARC) under group 2B carcinogens as possibly carcinogenic to humans [45].

 Cr6+ is regarded as cancer-causing agent and is toxic [17]. It is corrosive to skin and causes denaturation and precipitation of tissue proteins. Chronic exposure may lead to cancer of the respiratory tract [17] and should be controlled in such a manner that no person is exposed to carcinogenic chromium (VI) at concentrations greater than 25 mg/m3 of air, determined as the time-weighted average (TWA) concentration limit for up to a 10-hour workday or a 40-hr work week, over a working lifetime [44]. Chronic inhalation of manganese dust or fumes can cause manganism, a nonfatal disease which affects the central nervous system. The symptoms are mental disorder and disturbance in speech [45].

Mercury can cause both chronic and acute poisoning. Case control studies have shown effects such as tremors, impaired cognitive skills and sleep disturbance in workers with chronic exposure to mercury vapour even at low concentrations in the range 0.7–42 μg/m3 [46, 47]. A study has shown that acute exposure (4–8 hours) to calculated elemental mercury levels of 1.1–44 mg/m3 resulted in chest pain, dyspnoea, cough, haemoptysis, impairment of pulmonary function and evidence of interstitial pneumonitis [48]. Occupational exposure has resulted in broad-ranging functional disturbance, including erythrism, irritability, excitability, excessive shyness and insomnia. In regular and consistent use, a fine tremor develops and may escalate to violent muscular spasms. Long-term, low-level exposure has been

associated with more subtle symptoms of erythrism, including fatigue, irritability, loss of memory, vivid dreams and depression [49, 50].

In 2006, the United States Food and Drug Administration revoked the approval of the use of hydroquinone and proposed a ban on all over-the-counter preparations [51], because it felt that hydroquinone cannot be ruled out as a potential carcinogen. The reason was based on the absorption in humans and the incidence of neoplasm in rats shown by several studies in which adult rats showed increased rates of tumour development [51].

Extensive literature documentation reveals that hydroquinone can cause exogenous ochronosis, a disease that deposits blue-black coloration on the skin, if taken orally; but skin preparations containing the ingredient are administered topically [51, 52]. Although proper use of hydroquinone as skin lightening agent can be effective, it causes skin sensitivity. The effect can be minimized by daily use of sunscreen with a high persistent pigment darkening (PPD) rating. Hydroquinone can be combined with alpha hydroxy acids which exfoliate the skin to quicken the lightening process. In the United States, skin creams usually contain up to 2% of hydroquinone, but higher amounts up to 4% or above should be prescribed and used with caution.

The most trending research and publication shows that minor constituents of other chemicals such as phthalates, parabens and phenols in personal care products (shampoos, toothpaste, soap, etc.), though not extensively discussed, can cause early puberty in young girls and boys. The chemicals can enter the body by cutaneous penetration through the skin, inhalation or accidental ingestion. A worrisome aspect is that exposure is very much possible through mothers during pregnancy and breastfeeding [53].

#### **6.1 Skin depigmentation**

In human medicine, hydroquinone is used as a topical application in skin whitening to reduce the colour of skin by decreasing the production of melanin pigment in the skin. Since hydroquinone lightens the skin by reducing melanin, it simultaneously increases exposure of the skin to UV rays, thereby increasing skin cancer risks due to UV exposure [54]. It does not have the same predisposition to cause dermatitis as metals do. This use is banned in some countries, including the member states of the European Union under Directive 76/768/EEC: 1976 [55].

#### **6.2 Mechanism of whitening agent**

Clinical trials and experimental results prove that corticosteroids can cause permanent eye damage by inducing central serous retinopathy (CSR) or central serous

#### *Review of Health Hazards and Toxicological Effects of Constituents of Cosmetics DOI: http://dx.doi.org/10.5772/intechopen.84590*

chorioretinopathy (CSC) [56]. Different steroid medications, from anti-allergy nasal sprays (Nasonex, Flonase) to topical skin creams, eye drops (Tobradex) and prednisone, have been implicated in the development of CSR [57].

Corticosteroids have been applied on people with traumatic brain injury. In a systematic study in which the authors recommended that people with traumatic head injury should not be routinely treated with corticosteroids [58], side effects, such as cutaneous addiction with the development of uncomfortable and unsightly dermatoses, can occur with just one 15 g tube of moderate steroid over a period of 1 year [59].

 The use of corticosteroids have severe side effects such as steroid psychosis [60], hyperglycaemia, insulin resistance, diabetes mellitus, osteoporosis, cataract, anxiety, depression, colitis, hypertension, ictus, erectile dysfunction, hypogonadism, hypothyroidism, amenorrhoea and retinopathy [61]. Evidence for corticosteroids causing peptic ulceration is relatively poor except for high doses taken for over a month [62]; majority of doctors as of 2010 still believe this is the case and would consider protective prophylactic measures [63]. Corticosteroids have a low but significant teratogenic effect, causing a few birth defects per 1000 pregnant women treated. Corticosteroids are therefore contraindicated in pregnancy [64].

Nitrosamine has been established to cause cancer in animal species, which suggests that it may also be carcinogenic in humans. Available prove from case-control studies on nitrite and nitrosamine intake implicates it in gastric cancer (GC) risk and oesophageal cancer (OC) [28].

 According to Lautenschläger [27], there is no hard evidence on carcinogenic effect of nitrosamine-contaminated products applied on the skin. The study suggests that it is limited to nitrosamines inhaled with cigarette smoke or those formed by sodium nitrite from nitrite cured food reacting with secondary amines from vegetables or other food components. The study stated that although there is no 100% protection, as secondary amines and nitrite also occur in the natural environment, however, as far as cosmetic products are concerned, it should be taken care that nitrosamines and their co-chemicals such as secondary amines and nitrites are not used in the formulation. It may be a fact that health risk involved with contaminated surface body care products may be ignored as they are not supposed to remain on the skin. Also, consumers can now hive a sign of relief by drawing attention to the fact that the human system is equipped with its own secondary amines; therefore the skin can fight off any so as to protect itself with its natural moisturizing factor (NMF) which mainly contains amino acids. Chemical constituents of these amino acids are regarded as primary amines that can interact with NO2, but when the molecule is destroyed in the process, nonhazardous nitrogen is normally formed.

 Nitrite is approximately 10 times more toxic than nitrate [65], and interaction of nitrite with haemoglobin occurs in the blood as methaemoglobin is formed; this compound drastically lowers oxygen carrying capacity of the blood; when this happens, it results to methaemoglobinemia or 'blue baby syndrome' in infants; this is caused by lack of acidity condition in the intestinal walls of infants that is supposed to kill or reduce the bacteria; as a result these bacteria convert nitrate into nitrite. The most outstanding symptom of methaemoglobinemia is the appearance of a bluish colouration on the skin around the eyes and mouth as evidence of shortage of blood. The medical condition is treatable on early detection using methylene blue injection, which changes methaemoglobin back to haemoglobin, but death is sure when over 70% of the body's haemoglobin has been replaced by methaemoglobin [29].

Exposure to heat can cause damage to any cosmetic or makeup products. It changes the chemical formula, evaporates water and separates oil composition from other ingredients (an occurrence referred to as creaming) [66]. It also encourages the emergence of a culture medium for bacteria. The effect of these changes on the skin is harmful as such cosmetic product would no longer satisfy its optimal role [67].

#### **7. Conclusions**

 We conclude that apart from mercury, steroids and hydroquinone, a variety of other poisonous chemicals which are prohibited by many country's regulatory authorities are still present in many cosmetics. In many cases, cosmetic product manufacturers, importers and marketers conceal the real constituent of cosmetics by not listing them in the product label. Cosmetic and skin lightening products are in high usage in every country of the world, especially among women of all ages, even with the knowledge of hazardous effect it possess to human health. Skin rashes, multiple stretch marks, yellowish brown colouration, hypertension, diabetes mellitus, renal failure and cancer are some of the toxicological and health hazards associated with cosmetic product usage and are linked to poisonous substances used in cosmetic preparation.

#### **Author details**

John Kanayochukwu Nduka1 \*, Henrietta Ijeoma Kelle2 and Isaac Omoche Odiba3

1 Environmental Chemistry and Toxicology Research Unit, Pure and Industrial Chemistry Department, Nnamdi Azikiwe University, Awka, Nigeria

2 Department of Pure and Applied Science, Faculty of Sciences, National Open University, Abuja, Nigeria

3 Department of Chemistry, Alvan Ikoku Federal College of Education, Owerri, Nigeria

\*Address all correspondence to: johnnduka2000@yahoo.co.uk

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Review of Health Hazards and Toxicological Effects of Constituents of Cosmetics DOI: http://dx.doi.org/10.5772/intechopen.84590* 

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#### **Chapter 5**

## Mechanism and Health Effects of Heavy Metal Toxicity in Humans

*Godwill Azeh Engwa, Paschaline Udoka Ferdinand, Friday Nweke Nwalo and Marian N. Unachukwu* 

#### **Abstract**

Several heavy metals are found naturally in the earth crust and are exploited for various industrial and economic purposes. Among these heavy metals, a few have direct or indirect impact on the human body. Some of these heavy metals such as copper, cobalt, iron, nickel, magnesium, molybdenum, chromium, selenium, manganese and zinc have functional roles which are essential for various diverse physiological and biochemical activities in the body. However, some of these heavy metals in high doses can be harmful to the body while others such as cadmium, mercury, lead, chromium, silver, and arsenic in minute quantities have delirious effects in the body causing acute and chronic toxicities in humans. The focus of this chapter is to describe the various mechanism of intoxication of some selected heavy metals in humans along with their health effects. Therefore it aims to highlight on biochemical mechanisms of heavy metal intoxication which involves binding to proteins and enzymes, altering their activity and causing damage. More so, the mechanism by which heavy metals cause neurotoxicity, generate free radical which promotes oxidative stress damaging lipids, proteins and DNA molecules and how these free radicals propagate carcinogenesis are discussed. Alongside these mechanisms, the noxious health effects of these heavy metals are discussed.

**Keywords:** heavy metals, toxicity, neurotoxicity, carcinogenesis, free radicals, health effects

#### **1. Introduction**

 Metals are natural constituents that exist in the ecosystem. They are substances with high electrical conductivity which voluntarily lose their electrons to form cations. Metals are found all over the earth including the atmosphere, earth crust, water bodies, and can also accumulate in biological organisms including plants and animals. Among the 35 natural existing metals, 23 possess high specific density above 5 g/cm3 with atomic weight greater than 40.04 and are generally termed heavy metals [1, 2]. Theses metals generally termed heavy metals include: antimony, tellurium, bismuth, tin, thallium, gold, arsenic, cerium, gallium, cadmium, chromium, cobalt, copper, iron, lead, mercury, manganese, nickel, platinum, silver, uranium, vanadium, and zinc [1, 2]. This category of metals termed heavy metals have not only been known for their high density but most importantly for their adverse effects to the ecosystem and living organisms [3]. Some of these heavy metals such as cobalt, chromium, copper, magnesium, iron, molybdenum, manganese,

 selenium, nickel and zinc are essential nutrients that are required for various physiological and biochemical functions in the body and may result to deficiency diseases or syndromes if not in adequate amounts [4] but in large doses they may cause acute or chronic toxicities.

These heavy metals are distributed in the environment through several natural processes such as volcanic eruptions, spring waters, erosion, and bacterial activity, and through anthropogenic activities which include fossil fuel combustion, industrial processes, agricultural activities as well as feeding [5]. These heavy metals do bioaccumulate in living organisms and the human body through various processes causing adverse effects. In the human body, these heavy metals are transported and compartmentalized into body cells and tissues binding to proteins, nucleic acids destroying these macromolecules and disrupting their cellular functions. As such, heavy metal toxicity can have several consequences in the human body. It can affect the central nervous function leading to mental disorder, damage the blood constituents and may damage the lungs, liver, kidneys and other vital organs promoting several disease conditions [6]. Also, long term accumulation of heavy metals in the body may result in slowing the progression of physical, muscular and neurological degenerative processes that mimic certain diseases such as Parkinson's disease and Alzheimer's disease [6]. More so, repeated long-term contact with some heavy metals or their compounds may even damage nucleic acids, cause mutation, mimic hormones thereby disrupting the endocrine and reproductive system and eventually lead to cancer [7].

This chapter will highlight on the various sources of heavy metals and the processes that promote their exposure and bioaccumulation in the human body. More focus will be laid on the various mechanisms that lead to heavy metal toxicity with emphasis on macromolecule and cellular damages, carcinogenesis, neurotoxicity and the molecular basis for their noxious effects. The various toxic effects along with the signs and symptoms of some heavy metals in the human body will be discussed.

#### **2. Sources of heavy metal exposure to humans**

Heavy metals are naturally present in our environment. They are present in the atmosphere, lithosphere, hydrosphere and biosphere [8]. Although these heavy metals are present in the ecosystem, their exposure to humans is through various anthropogenic activities of man. In the earth crust, these heavy metals are present in ores which are recovered during mining activities as minerals. In most ores heavy metals such as arsenic, iron, lead, zinc, gold, nickel, silver and cobalt exist as sulfides while others such as manganese, aluminum, selenium gold, and antimony exist as oxides. Certain heavy metals such as copper, iron and cobalt can exist both as sulfide and oxide ores. Some sulfides may contain two or more heavy metals together such as chalcopyrite, (CuFeS2) which contains both copper and iron. During these mining activities, heavy metals are released from the ore and scattered in open in the environment; left in the soil, transported by air and water to other areas. Furthermore, when these heavy metals are used in the industries for various industrial purposes, some of these elements are released into the air during combustion or into the soil or water bodies as effluents. More so, the industrial products such as paints, cosmetics, pesticides, and herbicides also serve as sources of heavy metals. Heavy metals may be transported through erosion, run-off or acid rain to different locations on soils and water bodies. As reviewed from [9], the sources of specific heavy metals are described below.

*Mechanism and Health Effects of Heavy Metal Toxicity in Humans DOI: http://dx.doi.org/10.5772/intechopen.82511* 

#### **2.1 Arsenic**

 Arsenic is the 20th most abundant element on earth and the 33rd on the periodic table. The inorganic forms such as arsenite and arsenate compounds are lethal to humans and other organisms in the environment. Humans get in contact with arsenic through several means which include industrial sources such as smelting and microelectronic industries. Drinking water may be contaminated with arsenic which is present in wood preservatives, herbicides, pesticides, fungicides and paints [10].

#### **2.2 Lead**

 Lead is a slightly bluish, bright silvery metal in a dry atmosphere. The main sources of lead exposure include drinking water, food, cigarette, industrial processes and domestic sources. The industrial sources of lead include gasoline, house paint, plumbing pipes, lead bullets, storage batteries, pewter pitchers, toys and faucets [11]. Lead is released into the atmosphere from industrial processes as well as from vehicle exhausts. Therefore, it may get into the soil and flow into water bodies which can be taken up by plants and hence human exposure of lead may also be through food or drinking water [12].

#### **2.3 Mercury**

The metallic mercury is a shiny silver-white, odorless liquid metal which becomes colorless and odorless gas upon heating. Mercury is used in producing dental amalgams, thermometers and some batteries. Also, it can be found in some chemical, electrical-equipment, automotive, metal-processing, and building industries. Mercury can exist in a gaseous form thus it can be inhaled. Other forms of mercury contamination in humans may be through anthropogenic activities such as municipal wastewater discharges, agriculture, incineration, mining, and discharges of industrial wastewater [13].

#### **2.4 Cadmium**

This metal is mostly used in industries for the production of paints, pigments alloys, coatings, batteries as well as plastics. Majority of cadmium, about threefourths is used as electrode component in producing alkaline batteries. Cadmium is emitted through industrial processes and from cadmium smelters into sewage sludge, fertilizers, and groundwater which can remain in soils and sediments for several decades and taken up by plants. Therefore, significant human exposure to cadmium can be by the ingestion of contaminated foodstuffs especially cereals, grains, fruits and leafy vegetables as well as contaminated beverages [14, 15]. Also, humans may get exposed to cadmium by inhalation through incineration of municipal waste.

#### **2.5 Chromium**

Chromium is a metal that is present in petroleum and coal, chromium steel, pigment oxidants, fertilizers, catalyst, oil well drilling and metal plating tanneries. Chromium is extensively used in industries such as wood preservation, electroplating, metallurgy, production of paints and pigments, chemical production, tanning, and pulp and paper production. These industries play a major role in chromium pollution with an adverse effect on biological and ecological species [16]. Following the anthropogenic activities by humans, disposal of sewage and use of fertilizers may lead to the release of chromium into the environment [16]. Therefore, these

**Figure 1.**  *Pathway of heavy metals sources and exposure to humans.* 

 industrial and agricultural practices increase the environmental contamination of chromium. Environmental pollution by chromium has been mostly by the hexavalent chromium in recent years [17].

#### **2.6 Copper**

This is a heavy metal which is used in industries to produce copper pipes, cables, wires, copper cookware, etc. It is also used to make copper intrauterine devices and birth control pills. Copper in the form of copper sulfate is added to drinking water and swimming pools [18]. Due to man's anthropogenic and industrial activities, it can accumulate in the soil and up taken by plants. As such, copper is present in some nuts, avocado, wheat germ and bran etc.

#### **2.7 Manganese**

This metal is added to gasoline as methylcyclopentadienyl manganese tricarbonyl (MMT) and thus, gasoline fumes contain a very toxic form of manganese [19].


#### *Mechanism and Health Effects of Heavy Metal Toxicity in Humans DOI: http://dx.doi.org/10.5772/intechopen.82511*

*ppm, parts per million; mg, milligram; EPA, Environmental Protection Agency; OSHA, Occupational Safety and Health Administration; FDA, Food and Drug Administration.* 

#### **Table 1.**

*Regulatory limit of selected heavy metals.* 

#### **2.8 Nickel**

 It is used in the production of batteries, nickel-plated jewelry, machine parts, nickel plating on metallic objects, manufacture of steel, cigarette smoking, wire, electrical parts, etc. Also, it can be found in food stuff such as imitation whip cream, unrefined grains and cereals, commercial peanut butter, hydrogenated vegetable oils, as well as contaminated alcoholic beverages [19]. The various sources of heavy metals are summarized in **Figure 1**.

#### **3. Route of exposure, bio-uptake and bioaccumulation of heavy metals in humans**

Humans may directly get in contact with heavy metals by consuming contaminated food stuffs, sea animals, and drinking of water, through inhalation of polluted air as dust fumes, or through occupational exposure at workplace [20]. The contamination chain of heavy metals almost usually follows this cyclic order: from industry, to the atmosphere, soil, water and foods then human [8]. These heavy metals can be taken up through several routes. Some heavy metals such as lead, cadmium, manganese, arsenic can enter the body through the gastrointestinal route; that is, through the mouth when eating food, fruits, vegetables or drinking water or other beverages. Others can enter the body by inhalation while others such as lead can be absorbed through the skin.

 Most heavy metals are distributed in the body through blood to tissues [21]. Lead is carried by red blood cells to the liver and kidney and subsequently redistributed to the teeth, bone and hair mostly as phosphate salt [20]. Cadmium initially binds to blood cells and albumin, and subsequently binds to metallothionein in kidney and liver tissue. Following its distribution from blood to the lungs, manganese vapor diffuses across the lung membrane to the Central nervous system (CNS). Organic salts of manganese which are lipid soluble are distributed in the intestine for fecal elimination while inorganic manganese salts which are water soluble are distributed in plasma and kidney for renal elimination. Arsenic is distributed in blood and accumulates in heart, lung, liver, kidney, muscle and neural tissues and also in the skin, nails and hair. The regulatory limit for some selected heavy metals is shown in **Table 1**.

#### **4. Mechanism of heavy metal toxicity**

#### **4.1 Heavy metal-induced oxidative stress and oxidation of biological molecules**

Certain heavy metals are known to generate free radicals which may lead to oxidative stress and cause other cellular damages (see [22] for review). The mechanism of free radical generation is specific to the type of heavy metal.

#### *4.1.1 Iron*

Iron is a useful heavy metal in the human body as it is a constituent of certain biological molecules like the hemoglobin and involved in various physiological activities. However, in its free state, iron is one of the heavy metals generally known to generate hydroxyl radical (OH• ) as shown below by the Fenton reaction.

$$\text{Fe}^{3+} \star \text{O}\_2^{-} \rightarrow \text{Fe}^{2+} \star \text{O}\_2 \tag{1}$$

Fe2+ + H2O2 → Fe3+ + OH• + OH− (Fenton reaction) (2)

Net reaction (Haber-Weiss reaction):

$$\text{O}\_2\text{}^- + \text{H}\_2\text{O}\_2 \rightarrow \text{OH}^- + \text{OH}^\* + \text{O}\_2 \tag{3}$$

In addition to the above reactions, the following reactions below can also occur:

$$\text{OH}^{\bullet} \text{ H}\_{2}\text{O}\_{2} \rightarrow \text{H}\_{2}\text{O} + \text{H}^{\bullet} + \text{O}^{2\bullet} \tag{4}$$

$$\text{OH}^{\bullet} \text{ + Fe}^{2+} \rightarrow \text{Fe}^{3+} \text{+ OH}^{\bullet} \tag{5}$$

$$\text{LCOOH} + \text{Fe}^{2+} \rightarrow \text{Fe}^{3+} + \text{LO}^{-} + \text{OH}^{\bullet} \tag{6}$$

Hydroxyl radical (OH• ) is the most common free radical generated by the oxidation of iron. OH• is capable of reacting with biological molecules such as proteins, lipids and DNA damaging them. When OH• reacts with guanine, a nitrogenous base of nucleic acids, it leads to the generation of 8-oxo-7,8-dihydro-20-deoxyguanosine (8-oxo-dG) and 2,6-diamino-5-formamido-4-hydroxypyrimidine (FAPy-G), in which the former is a good marker for oxidative damage [23].

 It is well documented that metal-induced generation of oxygen reactive species can attack polyunsaturated fatty acid such as phospholipids. The first of such observation was first presented by Bucher et al. [24] who showed that irongenerated OH• can oxidize lipid membranes through a process known as lipid peroxidation. Following his experimental observations, he proposed the following mechanism:

Steps of lipid peroxidation:

$$\text{Inition:}\,\text{Lipid} \star \text{R} \cdot \text{OH}^{\bullet} \rightarrow \text{Lipid}^{\bullet}\tag{7}$$

$$\text{Propagation} \colon \text{Lipid}^{\bullet} \twoheadrightarrow \text{Lipid - CO}^{\bullet} \tag{8}$$

$$\text{Lipid - CO + Lipid}^{\bullet} \rightarrow \text{Lipid - OOH + Lipid}^{\bullet} \tag{9}$$

$$\text{Termination:}\text{Lipid}^{\bullet}\text{ 4:}\text{Lipid}^{\bullet}\text{ }\rightarrow\text{Lipid - Lipid}\tag{10}$$

$$\text{Lipid - CO} \text{•} \begin{array}{c} \text{Lipid} \\ \text{•} \end{array} \text{Lipid - CO - Lipid} \tag{11}$$

At the initiation stage, the radical (R• )/OH• attacks the lipid membrane to form a radial lipid. This radical lipid further propagates the formation of peroxyl lipid radical by reacting with dioxygen molecule or with a lipid. This reaction further promotes damage of the lipid molecule. At the termination stage, two radical lipid molecules and/or with a peroxyl lipid radical reacts to form a stable lipid molecule. The major aldehyde product of lipid peroxidation is malondialdehyde and it serves as a marker for lipid peroxidation.

Generally, proteins are not easily damaged by H2O2 and other simple oxidants unless transition metals are present. Thus, protein damaged are usually metalcatalyzed and involves oxidative scission, bityrosine cross links, loss of histidine residues, the introduction of carbonyl groups, and the formation of proteincentered alkyl (R•), alkoxyl (RO•) and alkylperoxyl (ROO•) radicals [25].

#### *4.1.2 Copper*

Copper ions have been identified to participate in the formation of reactive oxygen species (ROS) as cupric (Cu2+) and cuprous (Cu1+) which can participate in oxidation and reduction reactions. The Cu2+ in the presence of biological reductants such as glutathione (GSH) or ascorbic acid can be reduced to Cu+ which is capable of catalyzing the decomposition of H2O2 to form OH• *via* the Fenton reaction [26] as shown below.

$$\text{Cu}^{\ast} \star \text{H}\_{2}\text{O}\_{2} \rightarrow \text{Cu}^{2+} \star \text{OH}^{\bullet} \text{ } \star \text{OH}^{\cdot} \text{ } \tag{12}$$

The OH• radical formed is capable of reacting with several biomolecules. Experimental studies confirmed that copper is also capable of inducing DNA strand breaks and oxidation of bases *via* oxygen free radicals [27]. Though *in vivo* studies have not revealed copper-induced oxidation of low density lipoprotein (LDL), *in vitro* studies clearly demonstrated LDL oxidation induced by copper [28].

#### *4.1.3 Chromium*

Chromium (Cr), particularly Cr4+ has been shown in *in vitro* studies to generate free radicals from H2O2 [29]. Also, *in vivo* studies were able to show the detection of free radicals due to chromium in the liver and blood of animals. It was observed that Cr5+ intermediates were generated as a result of one-electron reduction.

#### *4.1.4 Cobalt*

Cobalt (Co), particularly Co2+ has been shown to generate superoxide (• O2 −) from the decomposition of H2O2 [30].

$$\text{Co}^{2+} + \text{O}\_2 \rightarrow \text{Co}^\* + \text{O}\_2\text{"}^- \rightarrow \text{Co}^\* - \text{OO} \cdot \text{} \tag{13}$$

#### *4.1.5 Vanadium*

Vanadium is a heavy metal that occurs in various oxidative states and has been shown to generate free radical. In the plasma, vanadium (V) is rapidly reduced to vanadium (IV) by NADPH and ascorbic acid antioxidants which bind to plasma proteins for transportation [31].

$$\text{V}^{5\*} + \text{NADPH} \rightarrow \text{V}^{4\*} + \text{NADP}^{\*} + \text{H}^{\*} \tag{14}$$

$$\text{V}^{4\*} \text{ + O}\_2 \rightarrow \text{ V}^{5\*} \text{ + O}^{2\*} \text{-} \tag{15}$$

$$\rm V^{5\*} + \rm O\_2\rm \text{-} \rightarrow \ \rm [V^{5\*} \text{-} \bullet \rm O\bullet] \tag{16}$$

More so under physiological conditions at approximately pH of 7, V(IV) can generate OH• from the decomposition of H2O2 according to the Fenton reaction.

$$\rm V^{4\*} + H\_2O\_2 \rightarrow \rm V^{5\*} + OH^- + \rm \rm OH \tag{17}$$

#### *4.1.6 Arsenic*

Arsenic has also been shown to generate free radicals such as superoxide (O2•–), singlet oxygen (1 O2), nitric oxide (NO•), hydrogen peroxide (H2O2), the peroxyl radical (ROO•) [32], dimethylarsinic peroxyl radicals ((CH3)2AsOO•) and also the dimethylarsinic radical ((CH3)2As•) [33] in some studies though the mechanism for the generation of all these reactive species remains unclear.

#### **4.2 Heavy metal-induced carcinogenesis**

 Some heavy metals are known to have carcinogenic effect. Several signaling proteins or cellular regulatory proteins that participate in apoptosis, cell cycle regulation, DNA repair, DNA methylation, cell growth and differentiation are targets of heavy metals [34]. Thus, heavy metals may induce carcinogenic effect by targeting a number of these proteins. More so, the carcinogenic effects of certain heavy metals have been related to the activation of redox-sensitive transcription factors such as AP-1, NF-κB and p53 through the recycling of electrons by antioxidant network. These transcription factors control the expression of protective genes that induce apoptosis, arrest the proliferation of damaged cells, repair damaged DNA and power the immune system [22]. Metal signalization of transcription factor AP-1 and NF-κB has been observed in the mitogen-activated protein (MAP) kinase pathways where the nuclear transcription factor NF-κB, is involved in controlling inflammatory responses while AP-1 is involved in cell growth and differentiation [22]. The p53 protein is an important protein in cell division as it guards a cell-cycle checkpoint and control cell division [35]. Inactivation of p53 allows uncontrolled cell division and thus p53 gene disruption has been associated with most human cancers. Also, AP-1 and NF-κB family of transcription factors are involved in both cell proliferation and apoptosis, and also regulate p53. Heavy metals generated free radicals inside the cell selectively activates these transcription factors and thus, may suggest that cell proliferation or cell death may be related to the exposure to carcinogenic metals. There exist various mechanisms of heavy metal-induced carcinogenesis.

#### *4.2.1 Arsenic*

Arsenic-induced carcinogenic mechanisms include epigenetic alterations, damage to the dynamic DNA maintenance system and generation of ROS [36, 37]. Alterations of histones, DNA methylation, and miRNA are the key epigenetic changes induced by arsenic which have shown to possess potentials to cause malignant growth [37]. In vitro studies have shown arsenic to alter the expression of p53 protein which also led to decreased expression of p21, one downstream target [38]. Arsenic compounds have been shown in an *in vitro* cell line study to promote genotoxicity in humans and mice leucocytes [39]. Also, a methylated form of arsenic was shown to inhibit DNA repair processes and also generate ROS in liver and spleen as metabolic products [40]. Arsenic can bind DNA-binding proteins and disrupt the DNA repair processes thereby increasing the risk of carcinogenesis. For example, the tumor suppressor gene-coded DNA was suppressed when arsenic was bound to methyl-transferase [41]. Also, cancers of the liver, skin, prostate and Kupffer cell were associated with Arsenic poisoning.

#### *4.2.2 Lead*

The mechanism of lead-induced carcinogenic process is postulated to induce DNA damage, disrupt DNA repair system and cellular tumor regulatory genes through the generation of ROS [42]. Studies have supported with evidence that ROS generation by lead is key in altering chromosomal structure and sequence [42]. Lead can disrupt transcription processes by replacing zinc in certain regulatory proteins [42].

#### *4.2.3 Mercury*

Little is known on the potential of mercury to act as a mutagen or carcinogen. However, the proposed mechanism of mercury-induced cancer is through the generation of free radicals inducing oxidative stress thereby damaging biomolecules. Mercury has been shown to induce malignant growth through the generation of free radicals as well as disruption of DNA molecular structure, the repair and maintenance system [43].

#### *4.2.4 Nickel*

 Nickel has an extensive range of carcinogenic mechanisms which include regulation of transcription factors, controlled expression of certain genes and generation of free radicals. Nickel has been shown to be implicated in regulating the expression of specific long non-coding RNAs, certain mRNAs and microRNAs. Nickel can promote methylation of promoter and induce the down regulation of maternally expressed gene 3 (MEG3) thereby upregulating hypoxia-inducible factor-1α, two proteins which are known to be implicated in carcinogenesis [44]. It has also been demonstrated that nickel can generate free radicals, which contributes to carcinogenic processes [45].

#### *4.2.5 Cadmium*

Cadmium has been implicated in promoting apoptosis, oxidative stress, DNA methylation and DNA damage.

#### *4.2.6 Iron*

The main cause of cancer due to iron intoxication is through the generation of free radicals. A school of thought produced a mechanism for iron-induced cancer whereby bile acids (deoxycholic acid), iron(II) complexes, vitamins K and oxygen interact to generate free radicals which induced oncogenic effect in the colon.

#### **4.3 Heavy metal-induced neurotoxicity**

Some heavy metals such as lead and manganese may affect the brain and cause neurological toxicity as reviewed from [46].

#### *4.3.1 Lead*

Lead toxicity is targeted towards the memory and learning processes of the brain and can be mediated through three processes. Lead can impair learning and memory in the brain by inhibiting the N-methyl-d-aspartate receptor (NMDAR) and can block neurotransmission by inhibit neurotransmitter release, block the neuronal voltage-gated calcium (Ca2+) channels (VGCCs) and reduce the expression of brain-derived neurotrophic factor (BDNF).

#### *4.3.2 Inhibition of NMDAR*

The NMDAR is known to enhance learning and memory mediated by the hippocampus [47] as this has been confirmed in animal studies in which animals exposed to lead during its developmental process exhibit similar learning deficits comparable to those with the absence or impaired NMDARs [48, 49]. In the hippocampus, NMDAR is a neural receptor which consists of two or more subunits; an obligatory NR1 subunit and one or more subunits from the NR2 particularly NR2A, NR2B and NR3 families. Lead has been shown to be a potent, non-competitive antagonist of the NMDAR [50–53], preferentially with high affinity at a regulatory site on the NR2A subunit [54]. This has been further supported in electrophysiological studies in which recombinant receptors for the subunits have shown NR2A-NMDARs to be more potently inhibited by lead than NR2B-NMDARs [55]. More so, lead has been shown to decrease the content of NR2A in the hippocampus and also alter the expression of NR1 spliced variants [56, 57] suggesting lead exposure disrupts the normal ontogeny of NMDAR.

#### *4.3.3 Reduction of neurotransmission*

 Lead can decrease neurotransmission as long term exposure of rats to low levels of lead has shown reduction in the release of Ca2+-dependent glutamate and γ-aminobutyric acid (GABA) in the hippocampus [58, 59]. This indicates dysfunction of presynaptic neuron signalization in the hippocampus as a result of lead exposure [60]. More so, lead exposure also impairs two postsynaptic currents; inhibitory post synaptic currents (IPSCs) and excitatory post synaptic currents (EPSCs) which are dependent on the release of presynaptic neurotransmitter such as glutamate and GABA. Thus, lead exposure leads to reductions in IPSCs and EPSCs indicating a deficit in glutamatergic and GABAergic neurotransmission systems. Also, lead has been shown to reduce the expression of key presynaptic proteins such as synaptobrevin (Syb) and synaptophysin (Syn) involved in vesicular neurotransmitter release [59, 60]. Lead can disrupt neurotransmission by inhibiting the neuronal voltage-gated calcium (Ca2+) channels (VGCCs) [61]. Thus, inhibition of presynaptic VGCCs may reduce the influx of Ca2+ which is required for fast release of vesicular neurotransmitter thus interfering with neurotransmission. It is now suggested that inhibition of either NMDARs or VGCCs by lead would result in

a significant decrease of Ca2+ influx into the cell. Reduction of Ca2+ entry into the cell will prevent neurotransmitter release and thus impair signalization leading to neurological disease states [62, 63]. Lead can also reduce the expression of brainderived neurotrophic factor (BDNF), a trans-synaptic signaling molecule that is released from both axons and dendrites which is involved in synaptic development and neurotransmitter release [64]. BDNF activity is also dependent on Ca2+ and thus has been implicated in the development of neurological diseases.

#### *4.3.4 Manganese*

 Manganese is known to accumulate in the mitochondria of neurons, astrocytes and oligodendrocytes cells and disrupts ATP synthesis [65] by inhibiting the F1/ F0 ATP synthase [65] or complex 1 (NADH dehydrogenase) of the mitochondrial respiration chain [66]. More so, it has recently been shown that manganese inhibits ATP synthesis at two sites in the brain mitochondria which are either the glutamate/ aspartate exchanger or the complex II (succinate dehydrogenase) depending on the mitochondrial energy source [67]. The disruption of ATP synthesis by manganese leads to decreased intracellular ATP levels and generation of free radicals thereby increasing oxidative stress [68] which may contribute to manganese cellular toxicity [69]. Furthermore, manganese can oxidize dopamine (DA) to react with quinone species thereby disrupting the dopaminergic system (for review, see [70]). This has been shown in animal studies were manganese exposure has led to specific deficits in the dopaminergic system [71]. The DA reactive species are taken up by the dopamine transporter (DAT1) thus causing dopaminergic neurotoxicity [72].

#### **4.4 Biochemical mechanism of heavy metal toxicity**

When heavy metals are ingested through food or water into the body, they are acidified by the acid medium of the stomach. In this acidic medium, they are oxidized to their various oxidative states (Zn2+, Cd2+, Pb2+, As2+, As3+, Ag+ , Hg2+, etc.) which can readily bind to biological molecules such as proteins and enzymes to form stable and strong bonds. The most common functional group that heavy metals bind is the thio groups (SH group of cysteine and SCH3 group of methionine). Cadmium has been shown to inhibit human thiol transferases such as thioredoxin reductase, glutathione reductase, thioredoxin *in vitro* by binding to cysteine residues in their active sites [73]. The equations of these reactions are shown below (see [74] for review) (**Figure 2**).

#### **Figure 2.**

*Reactions of Heavy metals with sulphydryl groups of proteins or enzymes (A) = Intramolecular bonding; (B) = Intermolecular bonding; P = Protein; E = Enzyme; M = Metal.* 

**Figure 3.**  *Reaction of arsenic with the thio group of enzymes.* 

In the above reaction, the oxidized heavy metal replaces the hydrogen of the SH group and the methyl of the SCH3 group thereby inhibiting the function of the protein or activity of the enzyme. For example, methylmercury (MeHg) strongly inhibits the activity of l-glutamine d-fructose-6-phosphate amidotransferase in yeast [75].

 Heavy metal-bound proteins may be a substrate for certain enzymes. In such situations, the heavy metal-bound protein fits into an enzyme in a highly specific pattern to form an enzyme-substrate complex and thus cannot accommodate any other substrate until it is freed. As such, the product of the substrate is not formed as the enzyme is blocked and therefore, the heavy metal remains embedded in the tissue leading to dysfunctions, abnormalities and damages in the body. Inhibition of thiol transferases lead to increased oxidative stress and cell damage. For example, toxic arsenic present in fungicides, herbicides and insecticides can attack –SH groups in enzymes to inhibit their catalytic activities as shown in **Figure 3**.

Also, heavy metal toxicity may be induced by the replacement of a metalloenzyme by another metal ion of similar size. Cadmium displaces zinc and calcium ions from zinc finger proteins and metalloproteins [76, 77]. For instance, cadmium can replace zinc in certain dehydrogenating enzymes, leading to cadmium toxicity. Such replacement can convert the enzyme structurally to an inactive form and completely alter its activity. These heavy metals in their ionic species such as Pb2+, Cd2+, Ag+ Hg2+ and As3+ form very stable biotoxic compounds with proteins and enzymes and are difficult to be dissociated.

 Heavy metals may also inhibit protein folding. This was first observed when heavy metals such as cadmium, lead, mercury and arsenite were shown to effectively interfere with the refolding of chemically denatured proteins [78]. It was also observed that when protein misfolded in the presence of heavy metals, the misfolded protein could not be rescued in the presence of reduced glutathione or EDTA chelator. The order of heavy metal in terms of their efficacy in folding inhibition is mercury > cadmium > lead and correlates with the relative stability of their monodentate complexes with imidazole, thiol and carboxylate groups in proteins [79].

 Heavy metal may cause proteins to aggregate as arsenite-induced protein aggregation was observed and shown to be concentration-dependent. Also, the aggregates contained a wide variety of proteins enriched in functions related to metabolism, protein folding, protein synthesis and stabilization [79]. *Saccharomyces cerevisiae* (budding yeast) cells was shown to accumulate aggregated proteins after it was exposed to equi-toxic concentrations of cadmium, arsenite and chromium (Cr(VI)) and the effect of protein aggregation was influenced by heavy metals in this order: arsenic > cadmium > chromium [80]. The *in vivo* potency of these agents to trigger protein aggregation probably depends on the efficiency of their cellular uptake/export and on their distinct modes of biological action. Summarized in **Figure 4** is the various mechanisms of heavy metal intoxication.

*Mechanism and Health Effects of Heavy Metal Toxicity in Humans DOI: http://dx.doi.org/10.5772/intechopen.82511* 

**Figure 4.**  *Mechanisms of heavy metal intoxication in humans.* 

#### **5. Health effects of heavy metal toxicity in humans**

Heavy metal toxicity can have several health effects in the body. Heavy metals can damage and alter the functioning of organs such as the brain, kidney, lungs, liver, and blood. Heavy metal toxicity can either be acute or chronic effects. Longterm exposure of the body to heavy metal can progressively lead to muscular, physical and neurological degenerative processes that are similar to diseases such as Parkinson's disease, multiple sclerosis, muscular dystrophy and Alzheimer's disease. Also, chronic long-term exposure of some heavy metals may cause cancer [7]. The various health effects of some heavy metals will be highlighted below.

#### **5.1 Arsenic**

 Arsenic exposure can lead to either acute or chronic toxicity. Acute arsenic poisoning can lead to the destruction of blood vessels, gastrointestinal tissue and can affect the heart and brain. Chronic arsenic toxicity which is termed arsenicosis usually focus on skin manifestations such as pigmentation and keratosis [81]. Lower level exposure to arsenic can cause nausea and vomiting, reduced production of erythrocytes and leukocytes and damage blood vessels, cause abnormal heart beat and pricking sensation in hands and legs. Long-term exposure can lead to the formation of skin lesions, pulmonary disease, neurological problems, peripheral vascular disease, diabetes mellitus, hypertension and cardiovascular disease [82]. Chronic arsenicosis may results to irreversible changes in the vital organs and possibly lead to death. Also, chronic arsenic exposure can promote the development of a number of cancers which include skin cancer, cancers of the bladder, lung, liver (angiosarcoma), and possibly the colon and kidney cancers [82]. Recently in the United States, the tolerable amount of arsenic in drinking water is 50 μg/liter but there is much concern of lowering this standard dose of population exposures to arsenic as the present dose is believed to increase the risk for cancer. Most environmental scientists studying this problem are of the view that the current tolerable limit of arsenic in drinking water or food be reduced.

#### **5.2 Lead**

 Toxicity due to lead exposure is called lead poisoning. Lead poisoning is mostly related to the gastrointestinal tract and central nervous system in children and adults [83]. Lead poisoning can be either acute or chronic. Acute exposure of lead can cause headache, loss of appetite, abdominal pain, fatigue, sleeplessness, hallucinations, vertigo, renal dysfunction, hypertension and arthritis while chronic exposure can result in birth defects, mental retardation, autism, psychosis, allergies, paralysis, weight loss, dyslexia, hyperactivity, muscular weakness, kidney damage, brain damage, coma and may even cause death [81]. Although lead poisoning is preventable, it still remains a dangerous disease as it can affect most of the organs of the body. Exposure to elevated levels of lead can cause the plasma membrane of the blood brain barrier to move into the interstitial spaces leading to edema [84]. Also, lead exposure can disrupt the intracellular second messenger systems and alter the functioning of the central nervous system. Developing fetuses and children are most vulnerable to neurotoxic effects due to lead exposure. A number of prospective epidemiologic studies in children less than 5 years of age have shown that low-level of lead exposure (5–25 μg/dL in blood) resulted to the impairment of intellectual development which was manifested by the lost of intelligence quotient points [85]. As such, the Centers for Disease Control (CDC) in the United States has reduced the tolerable amount of lead in children's blood from 25 to 10 μg/dL and recommended universal screening of blood lead for all children.

#### **5.3 Mercury**

Mercury is an element that can easily combine with other elements to form inorganic and organic mercury. Exposure to elevated levels of metallic, inorganic and organic mercury can damage the kidney, brain and developing fetus [86] while methyl mercury is highly carcinogenic. Organic mercury is lipophilic in nature and thus can easily penetrate cell membranes. Mercury and its compound affects the nervous system and thus increased exposure of mercury can alter brain functions and lead to tremors, shyness, irritability, memory problems and changes in hearing *Mechanism and Health Effects of Heavy Metal Toxicity in Humans DOI: http://dx.doi.org/10.5772/intechopen.82511* 

 or vision. Short-term exposure to metallic mercury vapors at higher levels can lead to vomiting, nausea, skin rashes, diarrhea, lung damage, high blood pressure, etc. while short-term exposure to organic mercury poisoning can lead to depression, tremors, headache, fatigue, memory problems, hair loss, etc. Since these symptoms are also common in other illness or disease conditions, diagnosis of mercury poisoning may be difficult in such cases [81]. Chronic levels of mercury exposure can lead to erethism, a disease condition characterized by excitability, tremor of the hands, memory loss, timidity, and insomnia. Also, occupational exposure to mercury as observed by researchers has been associated with measurable declines in performance on neurobehavioral tests of motor speed, visual scanning, visuomotor coordination, verbal and visual memory. Dimethylmercury is a very toxic compound that can penetrate the skin through latex gloves and its exposure at very low dose can cause the degeneration of the central nervous system and death. Mercury exposure to pregnant women can affect the fetus and offspring may suffer from mental retardation, cerebellar symptoms, retention of primitive reflexes, malformation and other abnormalities [87]. This has been confirmed in recent studies in which pregnant women exposed to mercury through dietary intake of whale meat and fish showed reduce motor neuron function, loss of memory, impaired speech and neural transmission in their offspring.

#### **5.4 Cadmium**

 Cadmium and its compounds have several health effects in humans. The health effects of cadmium exposure are exacerbated due to the inability of the human body to excrete cadmium. In fact, cadmium is re-absorbed by the kidney thereby limiting its excretion. Short-term exposure to inhalation of cadmium can cause severe damages to the lungs and respiratory irritation while its ingestion in higher dose can cause stomach irritation resulting to vomiting and diarrhea. Long-term exposure to cadmium leads to its deposition in bones and lungs. As such, cadmium exposure can cause bone and lung damage [88]. Cadmium can cause bone mineralization as studies on animals and humans have revealed osteoporosis (skeletal damage) due to cadmium. It has been observed that "Itai-itai" disease, an epidemic of bone fractures in Japan is due to cadmium contamination [89]. Increased cadmium toxicity in this population was found to be associated with increased risk of bone fractures in women, as well as decreased bone density and height loss in males and females. Cadmium is highly toxic to the kidney and it accumulates in the proximal tubular cells in higher concentrations. Thus, cadmium exposure can cause renal dysfunction and kidney disease. Also, cadmium exposure can cause disturbances in calcium metabolism, formation of renal stones and hypercalciuria. Cadmium is also classified as group 1 carcinogens for humans by the International Agency for Research on Cancer. Tobacco is the main source of cadmium uptake in smokers and thus, smokers are more susceptible to cadmium intoxication than non-smokers [90]. Also, cadmium can cause testicular degeneration and a potential risk factor for prostate cancer.

#### **5.5 Chromium**

Chromium, in its hexavalent form, is the most toxic species of chromium though some other species such as Chromium (III) compounds are much less toxic and cause little or no health problems. Chromium (VI) has the tendency to be corrosive and also to cause allergic reactions to the body. Therefore, breathing high levels of chromium (VI) can cause irritation to the lining of the nose and nose ulcers. It can also cause anemia, irritations and ulcers in the small intestine and stomach, damage

 sperm and male reproductive system. The allergic reactions due to chromium include severe redness and swelling of the skin. Exposure of extremely high doses of chromium (VI) compounds to humans can result in severe cardiovascular, respiratory, hematological, gastrointestinal, renal, hepatic, and neurological effects and possibly death [91]. Exposure to chromium compounds can result in the formation of ulcers such as nasal septum ulcer which are very common in chromate workers. Exposure to higher amounts of chromium compounds in humans can lead to the inhibition of erythrocyte glutathione reductase, which in turn lowers the capacity to reduce methemoglobin to hemoglobin. *In vivo* and *in vitro* experiments have shown chromate compounds to induce DNA damage in many different ways and can lead to the formation of DNA adducts, chromosomal aberrations, alterations in replication sister chromatid exchanges, and transcription of DNA [92]. Thus, there are substantial evidence of chromium to promote carcinogenicity of humans as increase stomach tumors have been observed in animals and humans who were exposed to chromium(VI) in drinking water.

#### **5.6 Iron**

 Iron salts such as iron sulfate, iron sulfate heptahydrate and iron sulfate monohydrate are of low acute toxicity when exposure is through dermal, oral and inhalation routes. However, other forms of iron are of serious health problems. Iron toxicity occurs in four stages. The first stage which commences 6 h after iron overdose is marked by gastrointestinal effects such as vomiting, diarrhea and gastro-intestinal bleeding. The progression to the second stage occurs 6–24 h after an overdose and it is considered as a latent period of apparent medical recovery. The third stage commences between 12 and 96 h after the onset of clinical symptoms and is characterized by hypotension, shocks, lethargy, hepatic necrosis, tachycardia, metabolic acidosis and may sometimes lead to death [93]. The fourth and final stage usually occurs within 2–6 weeks of iron overdose. This stage is marked by the development of strictures and formation of gastrointestinal ulcerations. Meat is rich in iron and thus meat eating countries are at risk of cancer as excess iron uptake increases the risk of cancer. Asbestos contains about 30% of iron and thus workers who are highly exposed to asbestos are at high risk of asbestosis, a condition which is known to cause lung cancer. Iron is known to generate free radicals which are suggested to be responsible for asbestos related cancer. Iron-induced free radicals can initiate cancer by the oxidation of DNA leading to DNA damage [94].

#### **5.7 Manganese**

Although manganese is an essential metal for the body, it recently became a metal of global concern when methylcyclopentadienyl manganese tricarbonyl (MMT), which was known to be toxic was introduced as a gasoline additive. MMT has been claimed to be an occupational manganese hazard and linked with the development of Parkinson's disease-like syndrome of tremour, gait disorder, postural instability, and cognitive disorder [95]. Exposure to elevated levels of manganese can result in neurotoxicity. Manganism is a neurological disease due to manganese characterized by rigidity, action tremour, a mask-like expression, gait disturbances, bradykinesia, micrographia, memory and cognitive dysfunction, and mood disorder [96]. The symptoms of manganism are very similar to that of Parkinson disease. However, the main differences between manganism and Parkinson disease is the insensitivity of manganism to levodopa (l-DOPA) administration and also the differences in the symptoms and progression of the disease [97].

### **6. Conclusion**

 The exposure of heavy metals to humans involve various diverse forms through food and water consumption, inhalation of polluted air, skin contact and most important by occupational exposure at workplace. Though some heavy metals such as iron and manganese are essential for certain biochemical and physiological activities in the body, elevated level in the body can have delirious health effects. Most of the other heavy metals are generally toxic to the body at very low level. The main mechanism of heavy metal toxicity include the generation of free radicals to cause oxidative stress, damage of biological molecules such as enzymes, proteins, lipids, and nucleic acids, damage of DNA which is key to carcinogenesis as well as neurotoxicity. Some of the heavy metal toxicity could be acute while others could be chronic after long-term exposure which may lead to the damage of several organs in the body such as the brain, lungs, liver, and kidney causing diseases in the body.

### **Author details**

 Godwill Azeh Engwa1 \*, Paschaline Udoka Ferdinand2 , Friday Nweke Nwalo3 and Marian N. Unachukwu4

1 Biochemistry, Department of Chemical Sciences, Godfrey Okoye University, Enugu, Nigeria

2 Department of Environmental Biotechnology, Bio-resource Development Centre, National Biotechnology and Development Agency (NABDA), Abagana, Anambra State, Nigeria

3 Department of Biotechnology, Federal University, Ndufu-Alike Ikwo (FUNAI), Abakaliki, Nigeria

4 Department of Biological Sciences, Godfrey Okoye University, Enugu, Nigeria

\*Address all correspondence to: engwagodwill@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**101**

factors.

**Chapter 6**

*Azade Sari*

**Abstract**

**1. Introduction**

Nephrotoxic Effects of Drugs

Drug-induced nephrotoxicity is a renal dysfunction that occurs as a result of exposure to nephrotoxic drugs. It is a common problem in certain clinical situations such as underlying renal dysfunction, cardiovascular disease, diabetes, and sepsis. Drugs can cause mild to moderate nephrotoxic problems such as intrarenal obstruction, interstitial nephritis, nephrotic syndrome, acid-base and fluid-electrolyte disturbances, alteration in intraglomerular hemodynamics, inflammatory changes in renal tubular cells, tubulointerstitial disease, and renal scarring leading to acute or chronic kidney injury. Therefore, early detection of adverse effects of drugs as well as the clinical history of the patient, basic renal functions, drug-related risk factors, and nephrotoxic drug combinations must be well known in order to prevent

drug-induced nephrotoxicity and progression to end-stage renal disease.

**Keywords:** nephrotoxicity, drugs, drug interaction, acute kidney injury, chronic kidney injury, prevention strategies, nephrotoxicity biomarkers

Acute kidney injury is the deterioration of the renal function over hours or days, resulting in the accumulation of toxic wastes and the loss of internal homeostasis. It can be caused by numerous etiologies [1, 2], and medications are a relatively common cause of kidney injury among these injuries [3]. Drug-induced nephrotoxicity is a renal dysfunction that occurs as a result of direct or indirect exposure to nephrotoxic prescribed drugs, over-the-counter products, diagnostic agents, or alternative/complementary products (herbal remedies, natural products, nutritional supplements) that are widely available at most health food stores [3, 4]. Druginduced nephrotoxicity is an extremely common condition and is responsible for a variety of pathological effects on the kidneys [4]. Nephrotoxicity most commonly affects tubulointerstitial compartment and manifests either acute tubular injury (ATI) or acute interstitial nephritis (AIN). There is a growing incidence of druginduced glomerular disease, including direct cellular injury and immune-mediated injury [5]. However, kidney disease does not develop in all patients exposed to the various potential nephrotoxins [3]. The nephrotoxicity of medications, drugs, or other ingested substances is a complicated process that involves a combination of

Potential nephrotoxic effect of the drug, comorbid diseases or conditions (underlying renal dysfunction, cardiovascular disease, diabetes, immunologic diseases, sepsis, etc.), genetic determinants of drug metabolism and transport, immune response genes, drug dose and duration of therapy, drug characteristics (solubility, structure and charge), combinations of potential nephrotoxic drugs,

## **Chapter 6**  Nephrotoxic Effects of Drugs

*Azade Sari*

### **Abstract**

Drug-induced nephrotoxicity is a renal dysfunction that occurs as a result of exposure to nephrotoxic drugs. It is a common problem in certain clinical situations such as underlying renal dysfunction, cardiovascular disease, diabetes, and sepsis. Drugs can cause mild to moderate nephrotoxic problems such as intrarenal obstruction, interstitial nephritis, nephrotic syndrome, acid-base and fluid-electrolyte disturbances, alteration in intraglomerular hemodynamics, inflammatory changes in renal tubular cells, tubulointerstitial disease, and renal scarring leading to acute or chronic kidney injury. Therefore, early detection of adverse effects of drugs as well as the clinical history of the patient, basic renal functions, drug-related risk factors, and nephrotoxic drug combinations must be well known in order to prevent drug-induced nephrotoxicity and progression to end-stage renal disease.

**Keywords:** nephrotoxicity, drugs, drug interaction, acute kidney injury, chronic kidney injury, prevention strategies, nephrotoxicity biomarkers

#### **1. Introduction**

Acute kidney injury is the deterioration of the renal function over hours or days, resulting in the accumulation of toxic wastes and the loss of internal homeostasis. It can be caused by numerous etiologies [1, 2], and medications are a relatively common cause of kidney injury among these injuries [3]. Drug-induced nephrotoxicity is a renal dysfunction that occurs as a result of direct or indirect exposure to nephrotoxic prescribed drugs, over-the-counter products, diagnostic agents, or alternative/complementary products (herbal remedies, natural products, nutritional supplements) that are widely available at most health food stores [3, 4]. Druginduced nephrotoxicity is an extremely common condition and is responsible for a variety of pathological effects on the kidneys [4]. Nephrotoxicity most commonly affects tubulointerstitial compartment and manifests either acute tubular injury (ATI) or acute interstitial nephritis (AIN). There is a growing incidence of druginduced glomerular disease, including direct cellular injury and immune-mediated injury [5]. However, kidney disease does not develop in all patients exposed to the various potential nephrotoxins [3]. The nephrotoxicity of medications, drugs, or other ingested substances is a complicated process that involves a combination of factors.

Potential nephrotoxic effect of the drug, comorbid diseases or conditions (underlying renal dysfunction, cardiovascular disease, diabetes, immunologic diseases, sepsis, etc.), genetic determinants of drug metabolism and transport, immune response genes, drug dose and duration of therapy, drug characteristics (solubility, structure and charge), combinations of potential nephrotoxic drugs,

urine pH, metabolic disturbances, older age (>65 year), and female sex are the common risk factors for drug-induced nephrotoxicity [1–5].

#### **2. Preventive measures of drug-induced nephropathy**

Basic renal functions should be evaluated and patient's renal functions should be considered when prescribing a new drug.

Dosage adjustments of the drugs should be done according to the patient's basic renal functions.

Risk factors for nephrotoxicity must be corrected before initiation of therapy. Nephrotoxic drug combination should be avoided.

Adequate hydration before and during therapy must be ensured.

Whenever possible, equally effective nonnephrotoxic drugs should be used [4].

#### **3. Biomarkers of drug-induced kidney injury**

 Early detection of drug-induced kidney injury is vital. Traditional biomarkers such as creatinine (Cr) and blood urea nitrogen (BUN) are insensitive for monitoring renal safety. Thus, new biomarkers have been investigated for accurate diagnosis, risk assessment, adopting therapy, and improvement of clinical outcome. [4, 6–9] Serum Cr can raise in prerenal azotemia without tubular injury, and some factors such as muscle mass, total body weight, fluid status, age, gender, race, and drugs influence serum Cr levels [8]. There are novel biomarkers that are more sensitive and can detect renal damage earlier than serum BUN and Cr levels [4, 6–9]. It is clear that which marker indicates kidney damage, but it is not yet clear when they should be measured. Also it is not clear if these biomarkers should be used for clinical decision-making or what should be done when the levels are elevated. Further studies are required for the routine clinical use of these biomarkers [8]. **Table 1**  lists common novel biomarkers that are under investigation.

#### **3.1 Neutrophil gelatinase-associated lipocalin (NGAL)**

NGAL is an acute phase reactant, and it can raise in inflammatory conditions. It is expressed by tubular epithelial cells in response to injury and tubulointerstitial damage. It can be measured in both plasma and urine [8–13], but for early detection of acute kidney injury (AKI), increase in urine NGAL is more specific than increase in plasma NGAL [9]. Baseline renal functions, severity of AKI, and age influence the level of NGAL. Studies showed that plasma and urine NGAL levels rise 2 hours after the injury; thus, it is the strongest predictor of AKI [8, 9]. It is more sensitive in ischemic and toxic (tacrolimus, cisplatin, cyclosporine A, radiographic contrast agent) AKI. [9] NGAL levels can be a predictor of clinical outcomes of AKI (need for dialysis and mortality) [9, 11] and progression of chronic kidney disease (CKD) in adults [8, 10, 12, 13]. Urine excretion of NGAL may be increased by albuminuria [9].

#### **3.2 Cystatin-C (Cys-C)**

Cys-C is a protein that synthesized in all nucleated cells. It is freely filtered in the glomerulus and reabsorbed and catabolized completely in the proximal tubules without tubular secretion. It is an alternative parameter of serum Cr in the measurement of renal function [8–11, 13]. Serum Cys-C levels are not influenced

#### *Nephrotoxic Effects of Drugs DOI: http://dx.doi.org/10.5772/intechopen.83644*


#### **Table 1.**

*Summary of novel nephrotoxicity biomarkers.* 

by gender, age, total body weight, muscle mass, or race, but tubular reabsorption is decreased by marked albuminuria [9–11]. It is thought to be the best biomarker for early kidney injury and more reliable marker of renal function [8, 10, 11].

#### **3.3 Cyclophilins**

They are structural proteins and measured in urine and plasma. Elevated levels of cyclophilins indicate AKI [11].

#### **3.4 Kidney injury molecule-1 (KIM-1)**

KIM-1 is a transmembrane glycoprotein. After ischemic or toxic injury, its levels elevate and it helps to distinguish acute tubular nephritis (ATN) from prerenal azotemia and CKD. Elevated urine KIM-1 levels are highly specific for kidney injury, because it is only expressed in injured kidney [8–13]. Some studies suggest KIM-1 as an indicator of AKI transition to CKD, because high levels of KIM-1 are maintained during CKD progression [12].

#### **3.5 Interleukin-18 (IL-18)**

It is also known as interferon-γ (IFN-γ)-inducing factor and its urinary levels rise in ischemic and toxic AKI [9]. It predicts renal parenchymal injury [10]. Its

levels are higher in patients with ATN. Increased urinary levels of IL-18 are a predictor of poor outcome such as death and the need for short-term dialysis [8, 9]. According to some studies, urine IL-18 levels increase in contrast-induced AKI [12], 6–12 hours after administration of the radiocontrast agent [9].

#### **3.6 Cell cycle arrest biomarkers**

Insulin-like growth factor-binding protein 7 (IGFBP-7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) are the two biomarkers included in this group. They are measured in urine and can be used for risk stratification of AKI [8, 9]. According to some studies, the most important advantage of these biomarkers is that their levels are not affected by comorbid diseases such as CKD, diabetes, and sepsis [8].

#### **3.7 Liver-type fatty acid-binding protein (L-FABP)**

FABP is a cytoplasmic protein found in all tissues with fatty acid metabolism. In kidneys, liver-type (in proximal tubule) and heart-type (in distal tubule) FABP present. Studies showed that urinary L-FABP is a useful biomarker in ischemic and toxic (especially cisplatin toxicity and contrast-induced nephropathy) AKI [9, 10, 12]. Elevated urinary and plasma H-FABP levels are indicator of distal tubular injury [10].

#### **3.8 N-acetyl-beta-D glucosaminidase (NAG)**

It is an enzyme produced by the proximal tubular cells. It can be found in the urine in very small amounts in healthy people. It cannot be filtered by glomerulus; thus, elevated levels of urine NAG indicate tubular damage [9, 10, 12]. Studies showed that NAG is a useful, sensitive, and early biomarker of contrast-induced AKI and high urinary levels correlate with poor outcome [9]. Also, high urinary NAG levels have been showed to be an indicator of clinical and subclinical tubular damage after chemotherapy [10] and are a sensitive biomarker of acute oxidative stress [11].

#### **3.9 Midkine**

It is a heparin-binding growth factor. Although not studied well, it may increase in contrast-induced AKI [9].

#### **3.10 α- and π-glutathione S-transferase (α-GST, π-GST)**

They are cytosolic, microsomal, and membrane-bound enzymes. They are detoxification enzymes that present in kidney and many other organs. Some studies showed elevation in urine α-GST indicating epithelial necrosis in the proximal tubules and π-GST indicating epithelial necrosis in the distal tubules [9–11]. α-GST is thought to be a biomarker of proximal tubular necrosis of cisplatin-induced injury. α-GST and KIM-1 are sensitive biomarkers for predicting polymyxininduced nephrotoxicity [10].

#### **3.11 γ-Glutamil transpeptidase (γGT) and alkaline phosphatase (AP)**

They are two enzymes that may increase in urine in proximal tubular epithelial damage [9–11]. Some studies showed increased levels of γGT, 24 hours after

#### *Nephrotoxic Effects of Drugs DOI: http://dx.doi.org/10.5772/intechopen.83644*

contrast administration [9], and some showed that it may be a sensitive biomarker of acute paracetamol nephrotoxicity [11].

Alanine amino peptidase (AAP), lactate dehydrogenase (LDH), β-galactosidase, β-glucuronidase, and leucine aminopeptidase are the other enzymes that are used for nephrotoxicity biomarkers [10, 11].

#### **3.12 β-2-Microglobulin**

It is a low-molecular-weight protein. It is normally found in urine but increases in tubular injury secondary to antibiotic, analgesic, solvent, heavy metal, or pesticide poisoning. In these conditions, it has been proved to be a sensitive biomarker of renal tubular damage [9–13]. But it rapidly degrades in room temperature and urine pH < 6; therefore, its utility as a urinary biomarker is limited [12].

#### **3.13 α-1-Microglobulin**

It is a low-molecular-weight protein, and elevated urinary levels can be used as a biomarker of tubular injury [10–12]. It is resistant to pH changes; thus, it is a sensitive biomarker of proximal tubular dysfunction [12].

#### **3.14 Retinol-binding protein (RBP)**

It is a low-molecular-weight protein that functions in vitamin A transportation from the liver to other tissues. It is a sensitive biomarker in proximal tubular damage [9–11].

#### **3.15 MicroRNA (miRNA)**

Although not demonstrated well, some subgroups of miRNA (miRNA-30a, -30c, and -30e) may rise in serum and urine in the states of contrast-induced AKI [9].

#### **3.16 Clusterin**

It is a glycoprotein and may be used as a biomarker for cisplatin-induced nephrotoxicity [10]. Urinary clusterin levels may increase following drug-induced nephrotoxicity [13].

#### **3.17 Trefoil factor 3 (TFF3)**

It is another new biomarker of nephrotoxicity that is mainly expressed in kidneys. Studies showed marked decrease in urinary TFF3 after nephrotoxic AKI [13].

#### **4. Common nephrotoxic drugs**

#### **4.1 Antibiotics**

#### *4.1.1 β-Lactam antibiotics*

β-Lactam antibiotics include penicillins, cephalosporins, cephamycins, carbapenems, monobactams, and β-lactamase inhibitors, and these are among the most commonly prescribed antibiotics [14]. β-Lactam antibiotics, especially penicillins and cephalosporins, frequently cause hypersensitivity reactions. Methicillin and nafcillin are the prototypical drugs for hypersensitivity reactions associated with AIN. It is generally characterized by acute and severe renal failure. Hematuria, proteinuria, leucocyturia, and pyuria are seen in urinary sediment of affected patients. Hypersensitivity reactions such as fever, rush, and peripheral eosinophilia are commonly seen [5, 14].

Piperacillin-tazobactam and vancomycin must not be used concurrently; they may cause AKI. Cephalosporins may exacerbate the renal toxicity of aminoglycosides [14].

#### *4.1.2 Non-β-lactam antibiotics*

They can cause AIN. Rifampicin-induced AIN is dose dependent and is commonly associated with oliguric acute renal failure, hemolytic anemia, thrombocytopenia, and hepatitis. Approximately two-thirds of patients affected by rifampin-induced AIN require renal transplantation [5].

#### *4.1.3 Aminoglycosides*

Aminoglycosides are antibiotics used in the treatment of Gram-negative and *Staphylococcus aureus* infections [1]. Aminoglycosides commonly cause acute kidney injury during therapy. It typically manifests after 5–7 days of therapy. It is described as a rise in the plasma creatinine concentration of more than 0.5–1 mg/dL or 50% increase in plasma creatinine concentration from baseline [15].

 Tubular uptake of aminoglycosides is a saturable process; thus, a single daily high dose is preferable to divided low doses. Administration of aminoglycosides by this way will cause less nephrotoxic effect [4, 15, 16].

Aminoglycosides primarily affect proximal tubules [1, 16], and patients present with acute tubular necrosis, showing features such as nonoliguric acute renal failure [4]. Proximal dysfunction leads to loss of enzymes, proteins, glucose, calcium, potassium, and magnesium [1]. In some patients, distal tubular segments can be affected and this manifests as polyuria and hypomagnesemia. Most patients may recover but some progress to irreversible kidney damage, especially if the patient is hypovolemic, septic, or catabolic. Aminoglycoside nephrotoxicity risk factors are nearly the same as other nephrotoxic agents. In addition to common factors, higher creatinine clearances and hypoalbuminemia are also independent risk factors for aminoglycoside nephrotoxicity [9].

#### *4.1.4 Polymyxins/colistin*

Polymyxins are a group of antibiotics that are used for pan-resistant nosocomial infections, especially for *Pseudomonas* and *Acinetobacter* spp. They may cause nephrotoxicity by IV injection. The nephrotoxicity mechanism is ATN leading to acute renal failure (ARF) with hematuria, proteinuria, and oliguria.

According to data, colistin appears more nephrotoxic than polymyxin B. Colistin-induced nephrotoxicity may exacerbate by older age, preexisting renal insufficiency, hypoalbuminemia, and concomitant use of NSAIDs. There are limited data on the risk factors for polymyxin-B associated nephrotoxicity. Methoxyflurane and cefazedone may enhance the nephrotoxic effect of polymyxin-B. Methoxyflurane-polymyxin-B combination should be avoided, but polymyxin-B-cefazedone combination may be used by close monitoring renal functions. Also, polymyxin-B may enhance the nephrotoxic effect of bacitracin [17, 18].

#### **4.2 Analgesics**

Analgesic nephropathy is a CKD characterized by papillary necrosis and chronic interstitial nephritis. It is caused by prolonged consumption of analgesic agents. Hypertension is a common clinical finding. The major laboratory manifestations are hematuria, sterile pyuria, elevation in serum Cr levels, and anemia [19, 20].

#### *4.2.1 Nonsteroidal anti-inflammatory drugs (NSAIDs)*

NSAIDs lead to AIN, chronic interstitial nephritis and finally CKD [20, 21]. Risk factors that may increase the nephrotoxic effect of NSAIDs are congestive heart failure, age > 65 years, and preexisting renal disease [4, 21].

#### *4.2.2 Acetylsalicylic acid (ASA)*

When used alone, even if prolonged, acetylsalicylic acid is not thought to cause kidney damage. It aggravates the nephrotoxic effects of both phenacetin and acetaminophen; thus, it should not be used simultaneously with these drugs. Acetylsalicylic acid and acetaminophen combination leads to papillary necrosis and calcification. Acetylsalicylic acid and NSAID combination leads to ischemic injury [20].

#### *4.2.3 Acetaminophen (paracetamol)*

Oral and rectal forms of acetaminophen may cause nephrotoxicity with chronic overdose [12]. The incidence of renal dysfunction is related to the severity of the acetaminophen ingestion [22]. IV forms may cause oliguria in neonates, infants, children, and adults [23]. AKI, which is primarily ATN, is manifested by elevations of BUN and Cr along with proteinuria, hematuria, and granular and epithelial cell casts on urine analyses. Also vascular endothelial damage can occur. It may be used in severe renal impairment with caution and dosing must be adjusted. Renal functions spontaneously return to baseline within 1–4 weeks. Rarely dialysis may be required. There is no evidence that N-acetylcysteine has any protective effect on nephrotoxicity [22, 23].

#### **4.3 5-Aminosalicylates (5-ASAs)**

5-ASAs are used to treat inflammatory bowel diseases. They lead hypersensitivity reactions in multiple organs, especially in kidneys, leading to acute interstitial nephritis [5, 24, 25]. During 5-ASA therapy, regular monitoring of renal functions is recommended [24]. AIN occurs most commonly during the initial year of therapy and it is non-dose-dependent. But in some patients with inflammatory bowel disease, AIN may occur as a complication of the disease [5].

#### **4.4 Proton pump inhibitors (PPIs)**

Proton pump inhibitors are used to treat acid-related gastrointestinal disorders. According to recent studies, many side effects of proton pump inhibitors have been reported. One of the side effects of the drug is nephrotoxicity, especially acute interstitial nephritis. PPI is thought to be associated with increased chronic kidney disease and its progression [5].

Recently, more concerns have been raised for proton pump inhibitors about the risks of acute interstitial nephritis, chronic kidney disease, and end-stage renal disease, and similar adverse kidney effects, such as interstitial nephritis and acute

renal failure, have been attributed to histamine-2 receptor antagonists [26]. But according to a newly published review, these potential adverse effects of PPIs must be proven by demonstrable evidence [27].

#### **4.5 Interferon (IFN)**

 Interferons are cytokines that protect body against viral infections. Exogenous interferons are used to treat hepatitis B, hepatitis C and various malignancies (IFN-α), multiple sclerosis (IFN-β), and chronic granulomatous disease and malignant osteoporosis (IFN-γ). They may cause nephrotic syndrome with histological finding of minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) [5, 28, 29], and renal vascular injury [28].

#### **4.6 Bisphosphonates**

Bisphosphonates are used to prevent bone absorption. The oral forms are used to treat osteoporosis and are thought to be nonnephrotoxic. But IV forms (pamidronate and zoledronic acid) can cause nephrotoxicity. Some reports reveal MCD and FSGS—not otherwise specified (FSGS-NOS) after pamidronate therapy and some reveal collapsing—FSGS (C-FSGS) after IV zoledronate therapy [5, 30]. According to some reports, zoledronic acid mainly leads to ATN [29]. The severity of nephrotoxicity depends on dosing, infusion time, and total number of infusion. Ibandronate is thought to be safe for kidneys [30].

#### **4.7 Lithium**

Lithium carbonate is generally used to treat bipolar disorder. It causes multiple renal side effects, most commonly nephrogenic diabetes insipidus. Acute lithium toxicity causes ATN. Chronic lithium toxicity occurs after more than 10 years of therapy and most commonly causes chronic tubulointerstitial nephritis with distal tubular cysts and sometimes secondary glomerulosclerosis. Lithium also causes nephrotic syndrome and histological findings of MCD or FSGS. Rarely it leads to end-stage renal disease secondary to lithium-associated chronic tubulointerstitial nephropathy. Lithium may also lead to renal tubular acidosis and hypercalcemia [5, 29, 31].

#### **4.8 Antiangiogenesis drugs (AADs)**

AADs are used for treatment of cancers and neovascular eye disorders such as diabetic retinopathy, macular degeneration, and retinal vein occlusion. They cause nephrotoxicity by endothelial cell injury and thrombotic microangiopathy (TMA) [5, 29]. Clinical manifestations of AAD-associated TMA are proteinuria and hypertension [29].

#### *4.8.1 Chemotherapeutic agents*

#### *4.8.1.1 Mitomycin-C*

Mitomycin-C is an alkylating agent used for treatment of malignancies. It can lead to TMA and AKI. AKI is dose-dependent, and the risk of TMA significantly increases with the cumulative doses of >60 mg [5, 29]. While TMA can occur during therapy, it usually occurs several week, average 75 days, after last dosage [29].

#### *4.8.1.2 Gemcitabine*

 Gemcitabine is a pyrimidine antagonist that is used to treat a variety of malignancies. AKI is dose-dependent. Higher cumulative dose and prior exposure to other chemotherapeutic drugs increase the risk of TMA [5, 29]. AKI occurs almost in all patients treated with gemcitabine. TMA most commonly occurs weeks to months after initiation of therapy [29].

#### **4.9 Oxymorphone-hydrochloride**

Oral-extended release formulation of oxymorphone-hydrochloride is a longacting opioid that is used to treat moderate to severe pain. Some data reveal AKI and TMA secondary to IV abuse of the drug [5, 32].

#### **4.10 Levamisole**

Levamisole has been used in treatment of pediatric nephrotic syndrome, colon cancer, inflammatory bowel disease, and rheumatoid arthritis. It was removed from the market due to agranulocytosis side effect. But it is still available in illegal form mixed with cocaine. Levamisole may cause antineutrophil cytoplasmic autoantibodies (ANCAs)-associated vasculitis (AAV) [5]. It may also rarely lead to hyponatremia, Wegener's granulomatosis, and renal failure [33].

Also antithyroid drugs such as propylthiouracil, carbimazole, and methimazole, and an antihypertensive drug hydralazine may lead to AAV [5].

#### **4.11 Angiotensin-converting enzyme inhibitors (ACE-Is)**

Captopril is an ACE inhibitor that is used for treatment of hypertension and proteinuria. Kaptopril may be the only ACE-I leading to nephrotic syndrome [5].

#### **4.12 Anabolic androgenic steroids**

Anabolic androgenic steroids like testosterone and illicitly used forms may lead to CKD [34].

#### **4.13 TNF-α inhibitors**

TNF-α inhibitors are biologic agents. Based on renal biopsy and clinical findings, glomerulonephritis associated with systemic vasculitis (GNSV), glomerulonephritis in lupus-like syndrome, and isolated autoimmune renal disorder are the subgroups of autoimmune renal diseases that may be caused by TNF-α inhibitors [5].

#### **4.14 Gold salts**

Gold compounds have been used for treatment of rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis. Because of side effects, low efficacy, and high cost, newer medications take place of gold salts. Parenteral use 0f gold leads to proteinuria, and gold-induced proteinuria is an indication of gold discontinuation. With oral gold therapy, proteinuria is rare. Renal pathology shows membranous glomerulonephritis. This may progress to nephrotic syndrome in patients continuing gold therapy [5, 35, 36].

#### **4.15 Amphotericin-B**

Amphotericin-B is an antifungal agent that is the choice in immunocompromised patients. It causes AKI via the tubular cell toxicity [1].

Amphotericin-B damages membrane integrity by causing pores and increases membrane permeability, and this leads to distal renal tubular acidosis [16]. Risk factors for nephrotoxicity are similar as any toxic nephropathy, but sodium deficiency is important especially in patients taking diuretic therapy [4]. Preventive procedures of amphotericin-B nephrotoxicity include saline hydration before and after drug administration, use of liposomal formulations, limiting the duration of therapy, and considering a continuous low-dose infusion over a 24 hours' period [1].

#### **4.16 Calcineurin inhibitors**

Cyclosporine and tacrolimus cause reversible AKI by inducing afferent and efferent arteriolar vasoconstrictions. Persistent injury can lead to interstitial fibrosis and glomerulosclerosis, and this leads to irreversible chronic nephrotoxicity. Tacrolimus may cause TMA [16, 37].

#### **4.17 Cisplatin**

Cisplatin may affect glomeruli and distal tubule, but it primarily affects proximal tubules. It leads to tubular necrosis or tubulointerstitial disease. It may increase serum creatinine and decrease GFR and lead to hypomagnesaemia, hyponatremia, hypocalcemia, and hypokalemia. When administered with hypertonic saline, cisplatin is better tolerated [1, 4, 16].

#### **4.18 Cyclosporin-A**

Cyclosporin-A leads to acute reversible and chronic irreversible nephrotoxicity. Acute reversible form is seen most commonly in renal transplant recipients and manifests as acute renal failure. Chronic form typically manifests after 1-year therapy. Clinical features are marked decline in glomerular filtration rate (GFR), hypertension, mild proteinuria, and rarely hematuria [4].

#### **4.19 Ifosfamide**

Ifosfamide is an analog of cyclophosphamide [16] and is used in the treatment of solid tumors in both children and adults [1] Cyclophosphamide is not nephrotoxic, but ifosfamide is toxic to the tubular cell. It prefers proximal tubular toxicity and leads to Fanconi's syndrome [1, 16]. It may also affect glomerulus and decreases GFR. These impairments may lead to clinical manifestations including hypophosphatemic rickets, proximal and distal renal tubular acidosis, diabetes insipidus, and hypokalemia [1].

#### **4.20 Foscarnet**

Foscarnet is used for treatment of resistant cytomegalovirus (CMV) infections. It causes acute interstitial nephritis and intratubular crystal formation. Foscarnet may chelate with calcium and cause hypocalcemia [16].

#### **4.21 Methotrexate (MTX)**

 Methotrexate is an antiproliferative and immunomodulating agent that is widely used. Its high-dose regimen leads to AKI. It may cause cellular damage or crystal nephropathy. Hydration therapy and urine alkalinization can prevent the concentration of MTX to become too high in the tubules. Also toxic systemic concentrations caused by AKI can be prevented by leucovorin administered 24–48 hours after MTX [1].

#### **4.22 mTOR inhibitors**

mTOR inhibitors such as sirolimus or everolimus can worsen any significant underlying proteinuria in liver recipients with preexisting chronic renal disease [1].

#### **4.23 Vancomycin**

Vancomycin is an antimicrobial agent used in the treatment of Gram-positive infections. Vancomycin use is associated with nephrotoxicity. Nephrotoxicity range was as high as 50% in the past, but now it ranges about 1.0–42.6% by newer formulations. In addition to common nephrotoxicity risk factors, patients weight exceeding 101.4 kg, daily vancomycin dose over 4 g are also risk factors for vancomycin nephrotoxicity [38].

#### **4.24 BRAF inhibitors**

 The selective BRAF inhibitors vemurafenib and dabrafenib are used to treat metastatic melanomas. There are no data reported dabrafenib use causing acute kidney injury, but there are a few case series with vemurafenib. The Food and Drug Administration Adverse Event Reporting System (FAERS) reports renal toxic effect of both agents. Vemurafenib appears more nephrotoxic than dabrafenib. Although not clear, they are thought to cause tubular interstitial injury with hypokalemia and hyponatremia [39].

#### **4.25 Dekstran**

Dekstrans are used for volume replacement therapy and may cause acute kidney injury. Therefore, fluid status and urine output should be monitored closely [39].

#### **4.26 EDTA**

It is a chelating agent used to get rid of iron from the body. It may produce toxic effect that may be fatal. Genitourinary effects of EDTA are nephrosis, nephrotoxicity, occult blood in urine, and proteinuria [40].

#### **5. Contrast-induced nephropathy**

Contrast-induced nephropathy is defined as an increase in serum Cr level of greater than 0.5 mg/dL or 25% over baseline during a period of 12–48 hours after contrast administration and the exclusion of other causes of AKI [2, 41].

Contrast agents generally lead to reversible AKI. Histopathologic evidence generally shows ATN. Compared with other types of ATN, contrast nephropathy is usually characterized by relatively rapid recovery of renal function. Most patients are nonoliguric. If occurs, oliguria occurs immediately after the procedure. Other manifestations of acute kidney injury, such as hyperkalemia, acidosis, and hyperphosphatemia, may be present. The urinary sediment may show classical findings of ATN. Proteinuria is absent or mild [41].

Underlying chronic renal disease, diabetes, and nephrotoxic medications predispose patients to renal injury from contrast. If IV contrast is necessary, patients can be pretreated with N-acetylcysteine (600 mg twice daily for two doses before study and after study) and alkalinized IV hydration (three ampules of 50 mEq sodium bicarbonate in 1000 mL D5W solution). In most cases, Cr usually starts to decline within 3–7 days. Dialysis is rarely required for contrast-induced AKI [37].

#### **6. Crystal-induced nephropathy**

Crystal nephropathies cause mechanical obstruction, local intrarenal inflammation, and tissue injury. There are three subgroups of crystal nephropathies: renal ischemic, tubular injury, and obstructive nephropathy [42].

Crystal-induced acute kidney injury commonly occurs following the administration of drugs or toxins that are poorly soluble or have metabolites that are poorly soluble in the urine [3, 43]. Especially in volume depletion status, glomerular ultrafiltrate can be enriched with minerals, proteins, or drug metabolites. Acute accumulation can induce a sudden onset of crystal formation leading to AKI, and long-term accumulation can lead to CKD [3, 42].

Patiens with drug- related crystal- induced AKI are usually asymptomatic. Kidney injury usually manifests with increased serum Cr, accompanying with hematuria, pyuria, and crystalluria. Crystal-induced AKI is generally reversible by discontinuation of the drug. It may rarely progress to CKD and dialysis may be required.

Risk factors for crystal-induced nephropathies are intravascular volume depletion, underlying kidney or liver disease, and metabolic disturbances that change urinary pH [3, 43].

#### **6.1 Sulfonamide antibiotics**

Sulfadiazine and sulfamethoxazole are relatively insoluble in acid urine. Alkalinization of urine to a pH > 7.15 increases sulfadiazine solubility.

#### **6.2 Methotrexate**

 High-dose methotrexate can both precipitate in the tubules and cause direct tubular injury. Alkalinization of urine to a pH > 7 increases methotrexate solubility. Methotrexate-induced acute kidney injury is typically nonoliguric and often reversible.

#### **6.3 Indinavir**

It is a protease inhibitor used in the treatment of human immunodeficiency virus infection. Acidic urine pH (<6) increases indinavir solubility, but acidification of urine may be harmful; thus, it is not recommended.

#### **6.4 Ciprofloxacin**

It is a fluoroquinolone antibiotic and causes acute interstitial nephritis and crystal-induced nephropathy. Crystals precipitate in alkaline pH [43].

#### *Nephrotoxic Effects of Drugs DOI: http://dx.doi.org/10.5772/intechopen.83644*

The other drugs that may lead to crystal-induced nephropathy are acyclovir; protease inhibitors such as indinavir, atazanavir; foskarnet; megadose vitamin C; orlistat; oral sodium phosphate; purgatives; triamterene; and high-dose amoxicillin [2, 3, 16, 43].

#### **6.5 Acyclovir**

It is used in the treatment of herpes infections and sepsis in neonates. It can most commonly lead to crystal-induced nephrotoxicity and also to nephrotoxicity by direct tubular injury [21].

#### **7. Conclusion**

Many drugs both prescribed or over-the counter have potential to cause kidney damage. Therefore, some basic items such as past medical history, age and weight of the patient, drug-related risk factors, and nephrotoxic drug combinations should be taken into consideration before starting the treatment. If a nephrotoxic drug use is mandatory, patients should be followed up closely and frequently with appropriate biomarkers. Basic renal functions should be evaluated before treatment. The early detection of drug-induced nephropathies and application of the appropriate treatment methods are critical, because many patients recover when the drug is discontinued.

#### **Author details**

Azade Sari Abdi Sutcu Vocational School of Health Services, Cukurova University, Adana, Turkey

\*Address all correspondence to: azadesari@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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phar.1423

### *Edited by Ozgur Karcioglu and Banu Arslan*

Over 400 years ago, Swiss alchemist and physician Paracelsus (1493–1541) cited: "All substances are poisons; there is none that is not a poison. Te right dose diferentiates a poison from a remedy." Tis is ofen condensed to: "Te dose makes the poison." So, why are we overtly anxious about intoxications?In fact, poisons became a global problem with the industrial revolution. Pesticides, asbestos, occupational chemicals, air pollution, and heavy metal toxicity maintain high priority worldwide, especially in developing countries. Children between 0 and 5 years old are the most vulnerable to both acute and chronic poisonings, while older adults sufer from the chronic efects of chemicals. Tis book aims to raise awareness about the challenges of poisons, to help clinicians understand current issues in toxicology.

Published in London, UK © 2019 IntechOpen © tane-mahuta / iStock