Given the recent news regarding the Flint, Michigan, water supply and infrastructures around the United States, the effects of lead toxicity have become an increasingly important topic in the medical community. As the US infrastructure continues to age, secondary problems like the situation in Flint could become more common and widespread. Overall, lead levels have been declining since the 1970s with the elimination of lead-based gasoline and monitoring by the Centers for Disease Control and Prevention (CDC).
Lead toxicity most commonly results from exposure to lead-contaminated dust and soil containing lead-based paint. Lead occurs naturally in the environment and exists as 3 oxidation states, Pb0, Pb2+, and Pb4+, with Pb2+ being the most common. Absorption occurs primarily via the gastrointestinal tract using both passive diffusion and energy transport systems involved with calcium and iron absorption. Chronic lead ingestion and toxicity can have a significant global effect on the body, leading to serious health problems. Lead can be distributed throughout the body, including in the blood, lungs, brain, abdominal organs, bones, and teeth. According to the CDC, 94% of the total lead burden is distributed among mineralized tissues—bones and teeth. Once ingested, lead is primarily stored in bone as part of the hydroxyapatite crystals, having a preference for active sites of remodeling such as trabecular bone in children and cortical and trabecular bone in adults. Over time, lead is excreted by the urinary and gastrointestinal systems, with the greatest excretion being in fecal matter.
When examining affected populations, age plays a pivotal role in the side effects and can impact the amount of lead that the body absorbs on ingestion. The World Health Organization cautions that, even when exposed to low levels of lead, children can develop behavioral issues, have decreased intelligence, and have decreased attention span, while both children and adults can experience issues with hypertension, renal impairment, anemia, and immune toxicity. According to the CDC, 20% of ingested inorganic lead is absorbed in an adult and 50% of ingested inorganic lead is absorbed in a child; however, on an empty stomach, these values increase to 60% to 80% and 100%, respectively. As lead levels increase, symptom type and severity increase. This difference in absorption could have profound health implications for populations living in impoverished conditions. The prevalence of lead toxicity has been shown to be much higher among individuals of lower socioeconomic status. The CDC has reported a higher prevalence of lead toxicity among black children from low-income families living in cities, with a large proportion residing in older homes. Given the increased deposition of lead in mineralized tissues, this article focuses on the orthopedic manifestations of lead toxicity.
The relationship between lead absorption and calcium absorption has been well studied. Lead has been shown to mimic calcium and interfere with cell processes that are dependent on calcium. Changes in the intake of calcium have also been shown to have a dose-dependent inverse effect on the absorption of lead, with lead absorption increasing with decreasing calcium intake. After ingestion, lead can be incorporated into bones as part of the hydroxyapatite crystals. These crystals can remain as part of the bone for long periods, breaking down and releasing lead into the blood during times of physiologic and pathologic stress (eg, pregnancy and osteoporosis) due to the higher demand for calcium. This can lead to increased levels of lead in the blood at undesirable times (eg, potentially harming the development of the fetus in pregnant women or leading to impaired bone healing in osteoporosis-related fractures). Ultimately, this storage can lead to an ongoing negative effect on the body long after the initial exposure. At the cellular level, it is thought that lead can negatively affect bone formation and remodeling. Some factors important to bone growth and bone remodeling include transforming growth factor beta, collagen, osteoblasts, bone morphogenetic protein, and Smad pathways. Transforming growth factor beta causes mesenchymal cells to proliferate and synthesize proteoglycans and type II cartilage. It also causes osteoblasts to make collagen. Bone morphogenetic protein causes mesenchymal cells to differentiate and become chondrocytes or osteoblasts. This, in turn, promotes the formation of bone. Bone morphogenetic protein uses Smad intra-cellular signaling pathways to activate mesenchymal cells. Both factors contribute to stimulating chondrogenesis at the growth plate. It is thought that increased levels of lead in the blood can inhibit bone morphogenetic protein stimulation of Smad intracellular signaling pathways, in turn disrupting endochondral bone formation. Lead also alters transforming growth factor beta and parathyroid hormone peptide signaling, decreasing overall healing and growth potential. Carmouche et al assessed the healing of closed tibia fractures in mice with elevated levels of lead in the blood. Low levels of lead in the blood caused a delay in bridging cartilage formation, decreased type II and X cartilage production, and caused a 5-fold increase in cartilage formation with delay in vascular invasion, resorption, maturation, and calcification. Mice with exceedingly high levels of lead in the blood were found to have fibrous nonunions secondary to inhibition of progression of endochondral ossification. It was thought that lead targeted osteoblasts by suppressing alkaline phosphatase and type I collagen production and decreasing osteocalcin, a regulator of bone formation/remodeling and a biomarker of osteoblast activity. Tumor necrosis factor alpha, matrix metalloproteinase 9, and cyclooxygenase 2 are also thought to be affected by lead due to their importance in chondrocyte apoptosis, vascular invasion, and matrix calcification, respectively. These effects should be considered when treating patients with lead toxicity and addressing their fractures and expectations for healing.
Bone mineral density can play an important part in bone's resistance against fracture, especially in the elderly population. In those populations that have been exposed, lead may decrease bone mineral density. Exposure in pediatric patients, vs adult or elderly patients, can still pre-dispose to the development of osteoporosis. Campbell et al examined pediatric populations exposed to lead, comparing the effects of low vs high levels of lead in the blood and bone mineral density. High levels of lead in the blood were associated with significantly higher bone mineral density than low levels of lead in the blood. It was deduced that this may be due to lead accelerating bone maturation by inhibiting parathyroid hormone–related peptide and transforming growth factor beta, resulting in inhibition of the cellular signals that help slow down the rate of maturation of chondrocytes in endochondral ossification. This early bone maturation may lead to osteoporosis later in life due to a subsequent lower peak bone mineral density reached in childhood. In adults, the inhibition of parathyroid hormone–related peptide by lead is thought to prevent bone remodeling, due to increased apoptosis of osteoblasts, predisposing to osteoporosis. Conti et al showed that chronically exposed rats had decreased bone density and decreased yield point to failure for fracture. In a mouse model, Monir et al demonstrated that lead affected bone turnover by decreasing collagen maturity, decreasing bone crystal size, and increasing bone turnover with elevated osteocalcin levels, indicating a possible mechanism for increased fracture risk with lead poisoning. Using ovariectomized mice models, Lee et al explored the effects of lead on perimenopausal mammals. They demonstrated that strength, load, and energy absorption capacity were negatively affected in ovariectomized mice exposed to lead, indicating an impairment in bone structure. The application of impaired bone remodeling and the ability to heal should be analyzed regarding prevention and treatment of fragility fractures in the osteoporotic population exposed to lead.
In a woman who has been chronically exposed, lead stored in the bone can be released during pregnancy and can have a detrimental effect on the developing fetus. This can lead to congenital lead poisoning, resulting in a dense cranial vault and delayed skeletal and deciduous dental development. An inverse relationship between levels of lead in the blood and height and chest circumference has been demonstrated in children who are exposed to lead. There is also a decreased serum level of osteocalcin, which is a marker for osteoblast activity. A recent study using a rat pup model showed that lead exposure led to an early decrease in 25-hydroxyvitamin D, with a late increase in 1,25-dihydroxyvitamin D. This late increase was thought to be a compensatory increase for the lack of available 25-hydroxyvitamin D. Consequentially, an upregulation in the number of vitamin D receptors was found in the body, most likely to compensate for the lack of available vitamin D. Using cultures of mesenchymal stem cells and mice models, Zuscik et al found that exposure to lead caused toxicity to chondrogenesis and chondrocyte differentiation. Lead inhibits bone morphogenetic protein stimulation of the Smad pathway. Uninhibited, bone morphogenetic protein stimulation of the Smad pathway would stimulate chondrogenesis and maturation in mesenchymal cells. Furthermore, lead was found to disrupt endochondral bone formation, resulting in exposed mice having decreased longitudinal growth and growth plate abnormalities. Overall, this caused increased cartilage at the physes, decreased maturation, and persistence of cartilage, leading to reduced bone formation. These studies provide support for an inverse relationship between the level of lead in the blood and height in children due to excessive cell line commitment to the cartilage-producing cells and lack of maturation of the chondrocytes produced, preventing bone growth and formation. Other studies have further characterized the deleterious effects that lead has on pediatric bone growth. Burns et al examined the growth of a cohort of pubertal Russian adolescents with chronic lead exposure. Compared with the cohort without lead exposure, those with persistently elevated levels of lead in the blood had an average decrease in adult height of approximately 2.6 cm. Renzetti et al also assessed the effects of lead exposure in pediatric patients, focusing on the effect of lead exposure during pregnancy on the growth of the child. They identified a negative association between maternal third trimester level of lead in the blood and offspring height and weight for age. Further support for decreased pediatric growth was reported by Ronis et al in a rat model. They demonstrated that high levels of lead in the blood (67–192 µg/dL and 120–388 µg/dL) during puberty led to reduced somatic and longitudinal growth and bone strength. Ronis et al also exposed the rats to a growth hormone axis stimulator, L-dopa, which failed to reverse these effects. They studied the influence of other hormones by replacing estradiol and testosterone in pubertal rats but did not find results that were statistically significant. Another consideration regarding growth is the effect that lead levels have on the hypothalamic pituitary access. It has been demonstrated that the effects of lead on pediatric growth are likely multifactorial, as lead decreases the level of insulin-like growth factor; however, this could cause a delay in growth as opposed to an overall decrease in growth. Various studies support higher levels of lead in the blood during childhood being associated with reduced, problematic growth. This can be incidentally found on radiograph in areas of high bony turnover, such as the physes, presenting as metaphyseal lines and sclerosis (Figure 1). Incidental radiographic evidence of lead toxicity can be evident at areas of high bony turnover, such as the physes in pediatric patients. Anteroposterior (A) and lateral (B) views of the knee demonstrating evidence of radiographic findings of lead toxicity with subtle evidence of metaphyseal lines and sclerosis including subtle banding (arrows).
The CDC estimates that approximately 500,000 US children between 1 and 5 years old have been affected by lead toxicity. The Institute for Health Metrics and Evaluation reported that, in 2016, exposure to lead was responsible for 540,000 deaths and 13.9 million disability-adjusted life years worldwide, making diagnosing and screening for lead toxicity an important public health concern. Both the American Academy of Pediatrics and the CDC recommend that children have the level of lead in their blood checked at 1 and 2 years old. According to the CDC and the American Academy of Pediatrics, 10 µg/dL was previously considered significant, but new recommendations suggest that greater than 5 µg/dL should be the threshold. With the incorporation of screening protocols by the American Academy of Pediatrics and the CDC, data have shown that fewer than one-fourth of children eligible for screening are receiving screening. Several factors, including access to care and the cost of testing, are resulting in decreased screening. Owing to poverty, populations most affected by lead toxicity have limited resources. The consideration of socioeconomic status could help guide more effective diagnosis and treatment. Medicaid provides reimbursement for two screenings—one at 1 year of age and one at 2 years of age. In places where lead is endemic in the environment, children who are not eligible for Medicaid can be screened at specific CDC-funded locations. If lead is not endemic to the area, parents are responsible for the cost of screening. According to the American Academy of Pediatrics Council on Environmental Health, the treatment algorithm for a child with an elevated level of lead is based on the concentration. Children with levels above 5 µg/dL should be rechecked 6 to 12 months after the first test. If the level of lead in the blood is 15 to 44 µg/dL, retesting should be performed in 1 to 4 weeks. For levels above 44 µg/dL, retesting should be done in 48 hours or less. All at-risk patients should be counseled about lead exposure and how to minimize the risk. Obtaining an abdominal radiograph should be considered if there is the possibility of lead ingestion via paint chips or pica behavior. Chelation therapy should be started when concentrations are greater than 45 µg/dL. Many chelation agents are available. Health care providers who understand the side effects and who are familiar with the dosing of agents should direct therapy. Succimer, which is noninvasive and administered orally, is the first-line treatment; however, compliance has been shown to be poor due to its sulfur smell. If a child is not able to tolerate succimer, British anti-Lewisite, or disodium-calcium edetate, available in intravenous form, should be administered, with specific dosing based on body surface area (Table 1). Another chelation therapy option, although less effective, is D-penicillamine. After initial treatment, the level of lead in the blood is expected to be below 25 µg/dL; however, due to the mobilization of body stores of lead, the level can increase again. It is recommended that the level of lead in the blood be rechecked 7 to 21 days after therapy. If the rebound is within 5 µg/dL of the original treatment amount, another cycle is indicated. If the level remains low, biweekly followed by monthly rechecks are indicated to confirm treatment success (Figure 2). Finally, the American Academy of Pediatrics and the CDC recommend including dietary education and encouraging dietary intake of calcium and iron in areas where lead is endemic. Recommended Chelation Therapy for the Treatment of Lead Toxicity Treatment algorithm for lead toxicity. After initial treatment, the level of lead in the blood is expected to decline below 25 µg/dL; however, due to the mobilization of body stores of lead, it can elevate again. It is recommended that the level of lead in the blood be rechecked 7 to 21 days after therapy. If the rebound is within 5 µg/dL of the original treatment amount, another cycle is indicated.