Case Study 1

1. Introduction

Water is the basis of life and is essential for the survival of our species. Throughout history, man has settled near bodies of water, whether it is an ocean, lake or river. 66 miles northwest of Detroit, Michigan lies the city of Flint. Founded in 1855 and with a population of about 102,434 people, it is the 7^th largest city in the state of Michigan. Flint is a majority black city, with 40% of its people living in poverty (Cencus.gov).

Since 2013, Flint has been dealing with water contamination that has caused an uproar in the community. Residents are being diagnosed with high blood lead levels, which at high amounts is toxic and can seriously harm the individual. Flint’s lead contamination issue began in late 2012/early 2013, when city officials decided that switching from the Detroit Water and Sewerage Department (DWSD) to a new pipeline connected to the Karegnondi Water Authority (KWA) would save the city about $200 million over 25 years.

As the new pipeline was being built, the DWSD terminated its water service to Flint in April 2014 and Flint decided to use the water from the Flint River as a temporary source of water on April 25, 2014. The water was deemed to be safe to drink by the Mayor of Flint at the time, Dayne Walling, after independent tests on the drinking quality of the water from the river.

What is attributed to be the reason of the current crisis in Flint is the decision to not treat the water from the river with orthophosphate, a commonly used corrosion inhibitor, to prevent corrosion of the interior surface of the pipes. As observed in Figure 1, the chloride levels of the Flint River are so high and corrosive, that the river water still leeches very large amounts of lead from the pipes, even after treating the water with orthophosphate (Roy, 2015).

In this case study, we offer insight on the background of lead toxicity, the toxicokinetics and toxicodynamics of lead toxicity, lead toxicity diagnostics and prevention and treatments for lead toxicity.

Figure 1. Comparing lead corrosion between week 3 Detroit water, Flint water and Flint water with orthophosphate (Roy, 2015).

1. Lead (Pb)

Lead is ubiquitously present on Earth and is one of the most important materials in the industrial world, owing to its malleability, corrosive-resistance, high density and softness. Lead is known to be a toxic metal, however its useful properties make it hard to replace with other materials. This constant industrial use of lead has caused it to negatively affect its environment, due to its poor biodegradability and subsequent bio-accumulation in the environment. The use of lead in plumbing has a long history, yet due to its potential toxicity, it was banned for use in plumbing solder that would be used for drinking water.

Lead has two oxidation states, +2 and +4, and is utilized in its elemental form and as a compound for various applications. Elemental lead has been used to craft bullets since the initiation of the firearm. It was a suitable material to use because of its density and low price. Metal lead is also used in construction, art, batteries, and other fields, yet it is being phased out in many fields due to its toxic effects. Lead compounds have been used in paint, plastics, candles, semiconductors and more.

2. Sources of lead exposure

The sources of lead exposure at home have declined since regulations have been put in place to remove the use of lead in common products such as toys and paint, however there are still many sources of lead exposure, especially in the industrial world. As mentioned above, lead is a prime material for use in many industries and occupations such as: battery manufacturing, chemical industry, construction workers, demolition workers, foundry workers, jewelers, miners, smelters, plastics industry, printers, rubber industry and more (Staudinger, 1998).

3. Levels of lead toxicity

Like most toxicants, there are levels of lead toxicity which are determined by the dose and duration of exposure. Lead exposure has varying effects on an individual, depending on their age. Children are more sensitive to lead toxicity than adults, because the child is still developing. Additionally, lead toxicity severely targets the nervous system of the individual, which is why developing children are more at risk of lead toxicity than adults (Needleman, 2004). As seen in Figure 2, children and adults are affected differently at various concentrations of lead in their blood. It can be observed that at 10ug/dL of lead in a childs blood may lead to a decrease in IQ, hearing and growth (Staudinger, 1998).

Figure 2. Effects of lead on children and adults.

2. Toxicokinetics and toxicodynamics of lead

1. Risk factors

Several risk factors have been identified for higher lead toxicity. Pregnant women are very sensitive to lead poisoning due to lead crossing placenta barrier and pose harm to fetus like damaging vital organs. Moreover, high blood lead concentration may cause miscarriage or premature birth (Bellinger, 1987). Children under 6 years are the most susceptible group for lead toxicity since they can experience the toxic consequence of lead at lower doses because their bodies are growing (Chisolm, 1956). Some other risk factors include living in very old buildings, family members working with lead, ingestion of food contaminated with lead, living in low income area, or drinking contaminated water as in this case.

2. Toxicokinetics

The inorganic form of lead is absorbed slowly through the respiratory and the gastrointestinal tract and poorly through the skin depending on the rout of exposure. Absorption via the respiratory system usually occurs with industrial poisoning by inhalation of lead dust but the most common poisoning is due to lead ingestion and absorption on the GIT (Karri, 2008). Due to the various nature of lead compound, the gastrointestinal absorb it in a different manner but in general, adult absorb around 10–15 % while children absorb much higher amount that may reach 50% of ingested lead. The other form which is organic lead (tetraethyl lead) is found to be absorbed rapidly compared to the inorganic (Barbosa, 2005). Those numbers are critical since lead is absorbed in a higher amount specifically in children.

Since lead absorption is more common in the GIT via ingestion, several experiments had been done to study the corresponding factors. An overall conclusion that age and nutrition status are heavily contributed to the absorption. Younger age, low calcium in the diet, high fat diet, empty stomach, and iron deficiency increase the absorption of lead (Merill, 2007). This could justify why the four-year-old Carlito’s in our case starts to show unusual symptoms before older people.

Lung absorption is the second main route and its depend upon several factors like the solubility and the amount of inhaled lead, whether it inhaled through the nose or the mouth, breathing rate, respiratory tract structure, and lead form (organic or inorganic). Larger inorganic molecules attach to the cilia then ingested after transportation to the esophagus. Whereas smaller molecules are carried by the alveolar cells and both large and small inorganic molecules are partially absorbed. In case of organic lead, it’s completely absorbed by the lung due to kidney, liver, and different tissue disruption (Fujita, 2002).

Skin lead absorption depend on the time of exposure or contact frequency but it is insignificant compared to GI and lung absorption. Importantly, if lead transfer from hand to mouth, in this case it could be significant due to ingestion (Needleman, 2004).

Once lead is absorbed by the mentioned routes above, it enters the bloodstream approximately 99% is bound to erythrocytes and 1% is found in the plasma. Free unbound lead concentration is found to be 15000th of the total lead blood concentration. Since lead has a high affinity to sulfhydryl groups, around 60% of lead is binding to thiol-containing element and the rest is binding to proteins such as albumin. Furthermore, the higher affinity of lead to certain compound the longer half-life and lead half-life is different depending on the location. Lead deposition in bone has the longest half-life ranged from months to years then the lead in tissue followed by the lead in the blood (Katzung, 2015).

After lead absorption, it distributes to various tissue and organs. The highest concentration of lead is found in the bone and its increase with the bone density and male gender. another highest lead amount is found in nails and hair followed by connective tissue, kidneys, heart, and liver. In case of pregnancy, lead could be transferred to the fetus and cause a potential hazard (Bellinger, 2005).

lead clearance from the body follows a multi-compartment model, that mainly composed of blood and soft tissue, and the majority of the execrated lead is found in the urine and feces (Grant, 2009). Lead half-life is around 1 to 2 months in soft tissue and years in the bone (Patrick, 2006). Approximately, 70% of eliminated lead is found in the urine and smaller amount in the skin, bile, sweat, breast milk, and hair (Rubin, 2008).

3. Toxicodynamics

Chronic exposure of lead leads to its storage in the soft tissues like liver, kidney and brain. It also stores in bone marrow, teeth, hair and nails which is thought to be non-toxic (Wani, 2015; Dapul, 2014). It exerts neurotoxicity, renal toxicity, hematological toxicity, hepatotoxicity and cardiovascular complications even with low level lead exposure (Wani, 2015; Chen, 2016; Ye, 2016; Specht, 2016; Dapul, 2014; Menon, 2016).

Neurological Toxicity

Children are more vulnerable to low level lead toxicity due to 70% of lead absorption into bones which is 94% in adults and due to increased absorption into tissues through gut, cell growth. Neurological symptoms due to lead toxicity is depended upon age, onset, brain structure and enzymes. Higher level of lead exposure leads to distortion of brain structure due to inflammation, collagen synthesis, ventricular compression as well as distorted BBB which was observed in rodents (Menon, 2016). Generation of Reactive oxygen species (ROS) due to oxidative stress is one of the main mechanisms that is associated with lead induced toxicity. Oxidative stress can lead to increased levels of methane dicarboxylic aldehyde (MDA) which is a marker for lipid peroxidation and decreased glutathione levels in the brain. Inactivation of antioxidant enzymes such as GSH reductase, superoxide dismutase and catalase by lead because of its divalent cationic property to bind to sulfhydryl groups strongly leads to damage to the brain (Ye, 2016).  Oxidative stress protector such as nuclear factor (erythroid derived 2) (Nrf-2), can be affected by lead induced toxicity which was evaluated in Nrf-2/HO-1 knockdown rats using Nrf-2 activator t- BHQ (Ye, 2016). Genetic alterations are also seen with lead toxicity which affected the change in the expression of proteins responsible for neuronal development (Chen, 2016).

Renal Toxicity

Higher levels of lead toxicity can lead to Chronic kidney disease whereas lower levels can also impair proximal tubular function leads to increased serum creatinine which then leads to nephropathy upon chronic exposure and the individuals with kidney disease, diabetes, or hypertension at greater risk compare to healthy individuals (Dapul, 2015; Ekong, 2006).  Triggered oxidative stress in the renal proximal tubular epithelial cells by accumulated iron released through erythrophagocytosis which is indicated by increased PS- tagged (Phosphatidyl serine) erythrocytes in spleen, usually internalized in healthy erythrocytes also proven in vitro using rodent’s HK-2 cells (Role, 2015).

Hematological Toxicity

Low level lead toxicity (<10g/dL) can also culminates in anemia which is due to oxidative stress by a heme degrading enzyme (HMOX1) and the genes encodes the proteins that are responsible for heme synthesis bind to lead in erythrocytes such as - aminolevulinic acid dehydratase (ALAD) and Hemochromatosis (HFE), which regulates the uptake of metals such as iron and lead into the cells leads to iron deficiency (Ding, 2016). Lead also cause decreased absorption of calcium into bones by acting upon Vitamin-D receptor (Dapul, 2015; Ding, 2016).

Cardiovascular Toxicity

Elevated blood pressure is one of the risk factor to develop cardiovascular complications. Oxidative stress and the associated kidney damage has increased hypertension with lead induced toxicity which was measured using decreased glutathione level and albuminuria, creatinine clearance and kidney injury molecule-1 (KIM-1) as markers, in rodents (Wildemann, 2016). Upon cumulative lead exposure, incident of coronary heart disease is increased by observing genetic risk score (GRS) of genetic polymorphisms in several genes such as -aminolevulinic acid dehydratase, Hemochromatosis (HFE), Heme oxygenase-1 (HMOX-1), Vitamin D receptor, apolipoprotein (APOE) and glutathione S- transferase superfamily genes (Ding, 2016).

Other effects

Acute lead toxicity results in gastrointestinal disturbances, abdominal pain, constipation, nausea, vomiting, anorexia and it effects reproductive system as well (Wani, 2015; Dapul, 2014).

3. Lead toxicity diagnosis

1. Diagnostic tests for lead

• Blood lead level (BLL) test: This test can be readily done by using a finger stick capillary blood sample. False positive results are possible with poor sample collection; the source of error typically includes the contamination with environmental lead. A positive test (levels > 10 µg/dL) should be confirmed with a venous sample (Dapul, 2014).
• Free erythrocyte protoporphyrin (FEP) method: The FEP levels increase in lead poisoning as lead inhibits the mitochondrial enzyme ferrolactase and interferes with heme synthesis. However, its threshold for detection is higher, and can be detected if the BLL is above 35 µg/dL. Due to its lower sensitivity, it is not used to detect the lead poisoning, but is used in conjugation with BLL to distinguish between acute and chronic lead exposure. If the BLL is positive and FEP is normal, the intoxication is acute, if both are elevated, it is assumed as chronic toxicity (Dapul, 2014).
• Complete blood count (CBC): This test can detect the hypochromic microcytic anemia caused by lead. The basophilic stippling caused by lead is uncommon in children (Dapul, 2014).
• Hair samples: Hair sampling is a one of the common methods used to measure the exposure to heavy metals in the environment, which also includes lead. It is not currently used in United States as it is less sensitive than BLLs (Dapul, 2014).
• Imaging: Radiopaque foreign bodies are observed in the abdominal radiographs, which is helpful to detect the cases of acute lead poisoning. Radiographs of long-bones show the presence of radiodensities at the distal ends of bones, which are known as “lead lines.” The presence of lead lines indicates chronic lead exposure (Dapul, 2014).

2. Symptoms of lead exposure in children and adults

In most of the cases, children are asymptomatic of lead poisoning at the time of screening. The symptoms are usually nonspecific, which include irritability, loss of appetite and abdominal pain. A range of neurological symptoms may develop that includes developmental delays and frank encephalopathy. At BLL levels greater than 100 – 150 µg/dL can cause acute effects such as convulsions, ataxia, hyperirritability, unconsciousness or coma, and death. Behavioral changes are reported at BLLs greater than 10 µg/dL. Increased antisocial behavior, reduced IQ and educational performance were also reported in children (Dapul, 2014).

Hematologic symptoms include, hypochromic microcytic anemia and fatigue. Normocytic anemia associated with hemolysis can occur at exposure levels of BLL greater than 70 µg/dL. Lead nephropathy can occur at higher doses. Aminoaciduria, glycosuria, and hyperphosphaturia were reported at exposure levels even lower than 10 µg/dL due to the impairment of proximal tubular function (Dapul, 2014).

In adults, chronic lead toxicity is associated with poor sperm count, decreased sperm motility and sperm production. Low level exposure to led may cause premature births and low birth weights. Development of hypertension was also reported, but no major congenital anomalies were reported. Children of parents who exposed to lead are likely to develop learning disabilities. Headache, behavioral changes, weakness, decreased thinking ability and altered sleep patterns were reported in adults (Tong, 2000; Spivey, 2007).

4. Prevention and treatment of lead poisoning

1. Prevention

Lead poisoning is irreversible. Lead can readily effect children because their organs and organ system are in a developing state (Wani, 2015). The first and foremost thing to prevent the lead poisoning is to educate the people regarding how the lead effects the body, how it can contaminate the air, food and water and how the lead is infected from the other sources like paints, toys, food cans, cosmetics, ceramic utensils and soil (Lanphear, 2005).

Precautionary measures should be taken to prevent lead contamination. For the prevention of lead toxicity from sources like paints, we should avoid using paints which are made up with lead. As drinking is the significant source for lead poisoning, old water pipes which are made with lead or used lead soldering for manufacturing, should be replaced with new, lead free pipes. As old pipes are very prone to lead poisoning. Food containers which are used for the packing of food may also contains lead so those containers should be prohibited. Children hands should be washed after playing in soil or with toys which can also be sources of lead poisoning. The use of hot water in cooking should be avoided because hot water equipment’s are also source of lead contamination in water (Wani, 2015). During pregnancy, blood lead level should be tested so that we can stop the lead exposure to the fetus (Dapul, 2014). Environmental lead levels should also be measured frequently and causes of lead contamination should be avoided.

2. Treatment

Chelating agents are mostly used in the treatment of lead poisoning whose blood levels are between 45µg/dl and 75µg/dl, these agents are used to remove the lead concentration from the body. DMSA which is 2,3 dimercaptosuccinic acid, is a succimer which is most recommended in the treatment of lead poisoning (Dapul, 2014).

Dimercaprol also used to treat the lead poisoning with blood lead levels higher than 70µg/dL and has the capability to form a nonpolar compound when reacted with lead and gets eliminated in urine and bile (Dapul, 2014). CaNa2 EDTA is also used in the treatment of lead poisoning used along with dimercaprol.  Children with Higher blood lead levels more than 70 µg/dL can be treated with CaNa2 EDTA by administering intravenously (Dapul, 2014).

Antioxidants may be used in the new therapy for the treatment of lead poisoning (Wani, 2015). lead neurotoxicity can be treated with use of Nano-encapsulated antioxidant. NAC N-acetyl cysteine and N-acetyl cysteine amide can be also used in the treatment of lead poisoning which increases glutathione levels to treat neurotoxicity(Badala, 2008; Patrick, 2006).

5. Conclusion

To conclude, lead toxicity is an increasingly important factor when considering a disease that has come from one’s environment. Lead toxicity is something that can be prevented with the proper precautions and education, yet there is a fundamental lesson we can take away about lead toxicity from the case of Flint, Michigan. Over time, we have learned what materials will harm us in the short-term, as well as the long-term, and lead is one of those materials. It is very cost effective in industry in the short-term, but can be devastating to the user and the environment in the long-term and short-term, depending on how one is exposed to it. Those who made the decisions to switch water sources in Flint did so because for monetary purposes and did not take into consideration their old plumbing, which should have been a priority to change, as well as the almost immediate outcry of the community who were punished the most. Although USA has regulations and controls on the use of lead, there are many developing countries around the world who are utilizing lead for the same reason we did in the past. The field of materials engineering is growing rapidly and the development of a new material with many of the same properties of lead would propel many countries to develop and expand with safety.

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