Lead Toxicity: an Australian Perspective

Abstract

Plumbism refers to the clinical features of lead toxicity, a condition which has been identified and then forgotten in a depressingly cyclical fashion since ancient times. For the past 6000 years antiquarians have described the human use of lead despite the well documented and severe adverse effects of exposure. As the analytical methods of lead measurement bring improved detection capability, it is clear that there is no safe amount of lead in the body. Sadly, we continue to identify affected patients in contemporary Australia, including young children. While there is little evidence that chelation therapy improves outcomes in affected individuals, it is recommended for use in patients with acute encephalopathy or in those with particularly elevated levels. The paucity of evidence supporting active treatment of plumbism highlights the importance of primary prevention, particularly in our most vulnerable.

Introduction

Recently, the Australian Therapeutic Goods Administration was notified of lead contamination in a commonly prescribed potassium chloride supplement. Despite reassurance from the Department of Health, our laboratory received an influx of referrals from concerned clinicians. This is not the first time the Australian public has been exposed to medications adulterated with lead. This year alone there have been a handful of cases of acute lead toxicity secondary to contaminated opium.¹ These events prompted a review of the literature surrounding lead toxicity and the implications of this notification, particularly in the Australian context.

Lead, or plumbum (Pb), is a ubiquitous element that has the potential to cause devastating and varied effects on human health.² It has been recently proposed that environmental contamination is a result of at least 6000 years of human mining.^3,4 Improved detection capability has changed our awareness of the effects of exposure at seemingly low concentrations. Plumbism is a condition difficult to treat with no clear consensus on best management. Primary prevention is key, particularly for developing countries and disadvantaged populations where children and adults are at greatest risk.⁵ Through this review we uncovered many unique connections linking Australia and plumbism, from the clinical diagnosis to the analytical measurement and the many communities continuing to be exposed to lead contamination today.

A Brief History of Plumbism

As reviewed by Hernberg, historians have described the human use of lead over several millennia for its desirable qualities such as malleability, durability and resistance to corrosion.³ Notably, the Romans used it to enhance the sweetness of wine which inevitably led to an epidemic of plumbism.² Over the last century it has been used in house paint to improve durability and colour and in fuel for its anti-knocking effect, as reviewed by Howarth.⁶ Hernberg described the cyclical rediscovery of the toxic effects of lead in their review. Plumbism was documented in ancient times then overlooked until the end of the Middle Ages. It was thought to be first recognised in Egyptian papyrus scrolls for use in homicide. It wasn’t until the 1^st century AD that Dioscorides attributed lead exposure to the associated clinical manifestations of plumbism.²

The Australian Context

The first description of paediatric plumbism came towards the end of the 19^th century from two Australian physicians, Gibson and Turner.⁸ Gibson was the first to publish the connection between the clinical presentation and the lead content of house paint.⁹ Gibson and Turner, from their original account, both independently published further reports on lead poisoning which, after initially being ignored as an antipodean curiosity, resulted in the legislated reduction of lead in domestic paints in Australia during the 1960s.^8–10 Contaminated homes are those built prior to 1970 and can be found all over the country. The Australian Government has acknowledged this issue with the publication of a guide to renovating.¹¹ Following these legislated changes, leaded petrol was eventually banned nationally on 1 January 2002.¹²

Despite historical knowledge of the adverse effects of lead on human health, the Australian population continues to be exposed. There are three main cities in Australia where nonferrous lead is mined and smelted, with significant implications for residents: Mount Isa, Port Pirie and Broken Hill.¹³

In 2007, Queensland Health studied the lead levels of children living in Mount Isa aged between one and four years of age.¹³ Of 400 children tested, 11.3% had blood lead concentrations >0.48 μmol/L (10 μg/dL), with a higher proportion of Aboriginal and/or Torres Strait Islander children affected. Repeated sampling in this same age group in 2010 showed the percentage of children with levels >0.48 μmol/L (10 μg/dL) reduce to 4.8%. Concern was again raised regarding the higher proportion of Aboriginal and/or Torres Strait Islander children with elevated blood lead levels.¹³ Since these reports were published, the Centers for Disease Control (CDC) has reduced the actionable limit of blood lead to 0.24 μmol/L (5 μg/dL).¹⁴

More recently in 2017, a pilot study assessing the blood lead of 30 children aged between one and seven years of age living in Mount Isa was published.¹⁵ Using the updated actionable limit of 0.24 μmol/L (5 μg/dL), 40% either reached or exceeded this level. The authors again reported a higher proportion of Aboriginal and/or Torres Strait Islander children affected. Despite these findings spanning more than a decade, there is no annual, community-wide screening program currently operating in Mount Isa.

Port Pirie is another contemporary Australian example of environmental contamination from lead smelting beginning in 1889 and continuing today.¹⁶ The Government of South Australia has been compiling results of children’s blood lead levels, for those under five years of age, as part of a voluntary screening program beginning in 1984. They report that the blood lead geometric mean for children in the first half of 2018 was 0.20 μmol/L (4.2 μg/dL) overall and 0.27 μmol/L (5.5 μg/dL) for children aged two years old.¹⁶ This program is ongoing.

Broken Hill also has a voluntary screening program that has been in operation since 1991 in addition to screening cord blood since 1996.¹⁷ The most recently published results from this program are from 2016 where 697 children aged less than five years were screened. The geometric mean was reported as 0.28 μmol/L (5.9 μg/dL), again above the actionable limit. Similarly to results obtained from Mount Isa, a higher proportion of Aboriginal and/or Torres Strait Islander children were affected.¹⁷

Analytical Methods and Actionable Limits

At the end of the 19^th century a colorimetric method for lead analysis using a form of Nessler glass with sulphuretted hydrogen solution was described.¹⁸ We could not find any information on the specific laboratory techniques used in the initial Australian paediatric case reports but, fortunately, the responsible ‘analyst’ was identified which allowed us to speculate on this matter.⁹ John Henderson, the government analyst, was a Scottish-born and -trained analytical chemist who was acknowledged as a contributor to what must have been viewed then as cutting edge experimental research.^19,20 Colorimetric and volumetric quantification of lead were well established at this time and, in view of his education and proven expertise, it is likely that a variation of these techniques were used.^18,21 Needless to say, his results have successfully withstood scrutiny for more than a century! Although laboratories now measure lead with more sophisticated mass spectrometry and atomic absorption techniques, spot testing of paint samples based on the lead-sulphide colour reaction is still used.²²

Atomic absorption spectrometry (AAS) was developed by Australian CSIRO scientist Alan Walsh. The insight to focus rather on atomic absorption spectra as opposed to emission spectra famously came to him while gardening in his Melbourne bayside home.²³ In this technique, metallic atoms are atomised by heat and, in their ground state, absorb radiation at a very narrow bandwidth specific to their line spectrum. There is a consequential decrease in the intensity of the light beam exiting the lamp which is measured by a spectrometer.²

Inductively coupled plasma mass spectrometry (ICP-MS) is beginning to supersede AAS due to its superior detection capability, high throughput and the ability to measure multiple analytes concurrently. ICP is a hard ionisation technique with the desired outcome of complete atomisation. This method involves sample being nebulised into the ion source and then ionised into extremely hot plasma of approximately 10,000 Kelvin. The ions are then transmitted to the mass analyser (MS) for detection.²

The detection capability of the assay used to accurately measure very low concentrations is imperative. As analytical methods become more sophisticated and more data are published on the adverse effects at ‘low’ concentrations, it is expected that the CDC actionable limit will continue to reduce as it has over time.²⁴

While whole blood lead is the preferred sample for assessing toxicity, lead can also be measured in hair, urine and stool. There is also a point-of-care (LeadCare II, Meridian Bioscience) testing system which may be more acceptable to our younger population.¹⁵

Clinical Manifestations

‘One rarely sees a potter whose face is not cadaverous and has the colour of lead,’ is how Ramazzini described the clinical features of plumbism in 18^th century potters.^3,25 Plumbism can present with diverse clinical signs and symptoms.^2,26 Severity of these effects will depend on the degree and duration of the exposure and the individual’s blood lead concentration. In severe cases lead toxicity can be fatal (Figure 1).^2,26

Figure 1.

Clinical manifestations of lead toxicity (adapted from ref. 2).

Neurotoxicity

Neurotoxicity is a key feature. It is understood to be primarily caused by the replacement of divalent cations whereby lead is substituted for calcium ions allowing these ions to cross the blood brain barrier and accumulate affecting neural excitation, memory, cognitive performance and behaviour.^27–29 Oxidative stress, impairment of cell signalling and neurotransmission have also been thought to contribute.^27,28 Ocular neuritis, observed by Gibson in 1904, can be seen in severe cases.⁹

Of grave concern is the effect of lead on the developing brain. In children, the central nervous system is particularly vulnerable, impacting cognitive function at seemingly low blood concentrations.^29,30 A recent study examining the effect of lead on cognition and socioeconomic outcomes reported that childhood exposure was proportionately and significantly associated with reduced socioeconomic status and cognitive function in a New Zealand population.³¹ The authors examined patients at 38 years of age, making it the longest follow-up period to date assessing exposure in childhood.^31,32 In adults, it is primarily the peripheral nervous system that is affected, manifesting as peripheral neuropathy.^26,33 Encephalopathy, in both adults and children, has been well described at particularly high lead concentrations.

Neurotoxic effects are thought to occur in children at blood lead concentrations of <0.48 μmol/L (10 μg/dL) with reduced nerve conduction beginning at 0.97 μmol/L (20 μg/dL) and encephalopathy at 2.42 μmol/L (50 μg/dL). In adults, peripheral neuropathy is observed at blood lead levels of 0.97 μmol/L (20 μg/dL) with encephalopathy occurring at 4.83 μmol/L (100 μg/dL) (Figure 1).

Haematotoxicity

The haematological effects of plumbism are well established. Lead exposure can affect haem synthesis through inhibition of delta-aminolevulinic acid dehydratase (ALAD), coproporphyrinogen oxidase (CPOX) and ferrochelatase activity (Figure 2).² The resultant increase in urinary 5-aminolevulinate (ALA) and coproporphyin-III excretion can be similar to that seen in ALAD-deficiency porphyria.³⁴ The elevated red cell protoporphyrin that can occur in lead toxicity is not as well understood but may be due to an intramitochrondrial deficiency of ferrous iron. This remains elevated for the lifespan of the erythrocyte, making it a useful marker in addition to whole blood lead in monitoring patients with occupational lead exposure.³⁴ These effects are seen in both children and adults with blood lead concentrations >0.48 μmol/L (10 μg/dL).² When severe, the disruption of haem synthesis frequently results in anaemia which is typically hypochromic and microcytic with basophilic stippling of erythrocytes.^2,35 Frank anaemia is observed in both children and adults with blood lead levels >2.42 μmol/L (50 μg/dL) (Figure 1).²

Figure 2.

Effect of lead on haem biosynthesis (adapted from ref. 2).

Cardiotoxicity

Lead exposure is a well-known risk factor for cardiovascular disease. The effects on the cardiovascular system are likely due to many cellular and molecular mechanisms including but not limited to increased oxidative stress, inflammation, impairment of nitric oxide signalling, impairment of endothelial cell function and clotting.³⁶ More specifically, elevated blood lead levels have been associated with hypertension, peripheral vascular disease and cardiomyopathy but most recently with increased cardiovascular disease mortality.^36–40 Lanphear et al., in a provocative paper, concluded that in the US, low-level lead exposure (blood concentrations <0.32 μmol/L or 6.7 μg/dL) was an important yet underestimated risk factor for cardiovascular disease mortality with a contribution similar to that of smoking, hypertension and male gender.³⁷

Nephrotoxicity

Lead is primarily excreted by the kidneys thus causing nephrotoxicity in both acute and chronic exposure. Acute plumbism can result in proximal renal tubular damage with glycosuria and aminoaciduria from defects in solute and amino acid transport. In some cases patients can develop Fanconi symdrome.^26,41,42 Chronic plumbism manifests as both glomerular and tubulointerstitial dysfunction resulting in hypertension, hyperuricaemia and chronic renal failure.⁴³ Lead is thought to cause nephrotoxicity through oxidative stress mechanisms affecting renal cells.⁴² The nephrotoxic effects of lead have been observed at blood concentrations of >2.42 μmol/L (50 μg/dL) in children and >1.93 μmol/L (40 μg/dL) in adults (Figure 1).²

Gastrotoxicity

The chief route of lead absorption in the general population is gastrointestinal, causing symptoms including abdominal colic, nausea and vomiting in both acute and chronic toxicity. Elevated liver enzymes and low-density lipoproteins have also been observed in affected individuals.⁴⁴ A less common but well-known hallmark is Burton’s line, a bluish-purple track observed where the gingiva meets the teeth, and is thought to be caused by deposition of lead sulphide from circulating lead reacting with suphur ions produced by microbial activity.^45,46 Colic has been observed in children with blood lead >2.42 μmol/L (50 μg/dL) (Figure 1).²

Other Systems

Plumbism affects almost all physiological systems. Due to the role of bone as the main storage site of lead in the body, the skeletal system is adversely affected by exposure causing skeletal malformation and delay in dental development in children.⁴⁷ Lead has also been noted to affect vitamin D metabolism, further contributing to skeletal impairment.⁴⁸ Growth delay is thought to occur in children with blood lead concentrations <0.48 μmol/L (10 μg/dL).²

Lead may be carcinogenic, with the International Agency for Research on Cancer classifying inorganic lead compounds as ‘probably carcinogenic to humans’ and organic lead compounds as ‘possibly carcinogenic to humans’.⁴⁹

The reproductive system is thought to be affected by lead toxicity in both males and females. It has been described as a cause for miscarriage, low birth weight and even spontaneous abortion at particularly high concentrations.^26,50 In males, lead exposure has been linked with reduced sperm count, abnormal sperm morphology and reduced libido.^50–52 Infertility has been observed in adult males with blood lead >1.93 μmol/L (40 μg/dL).¹⁷

Lead is also understood to impair immunity by decreasing antibody production and suppressing cellular immune function and, finally, individuals with a history of exposure have altered lung function.^53,54

Management of Plumbism

Prior to the discussion of treatment and prevention, the kinetics of lead in the body must be addressed. The majority is stored in bone which directly interacts with an individual’s blood pool and thus accounts for the majority of the blood concentration for years after the source has been removed.⁵⁵ This is explained by the half-life of lead in the various human tissues: the half-life in blood is 35 days; in soft tissue it is 50 days; and in bone the half-life can exceed 20 years.^55,56 Thus, the first step in managing plumbism in all individuals is identifying the source, removing it and preventing further exposure.⁴⁸

Management in Children

Children, including the developing foetus, are more susceptible to toxicity compared to their older counterparts. The developing foetus can be exposed to lead crossing the placenta and again through breast milk following birth.^57–59 Furthermore, renal clearance in children is reduced, coupled with an increased uptake of gastric lead.⁶⁰ Iron deficient children are particularly susceptible to toxicity due to the increased activity of the divalent metal transporter 1 and a higher incidence of pica in this patient group.^61,62

The CDC has published recommendations for the management of affected children and recommend those with blood concentrations >2.1 μmol/L (44 μg/dL) should receive chelation therapy. In addition, children with evidence of acute ingestion (for example, from an abdominal x-ray) should be considered for bowel decontamination.⁶³ Further to this, the Australian Therapeutic Guidelines recommend immediate intravenous chelation therapy in any child presenting with lead encephalopathy and oral chelation therapy in any child without encephalopathy with a blood level >2.2 μmol/L (45 μg/dL).⁶⁴ In children with lower concentrations, there is no evidence that chelation therapy improves developmental outcomes.^65,66 All children should be assessed for iron deficiency and treated if indicated.^61,62

Due to the limitations regarding the management of toxicity, emphasis should be placed on preventing exposure. A Cochrane systematic review concluded that there was little evidence for educational and dust control interventions in reducing the blood levels of children. These interventions varied between studies and included patient education, dust control and soil abatement. However, they did identify a trend toward reducing the number of children with a blood level >0.72 μmol/L (15 μg/dL) through education interventions.⁵ The American Academy of Paediatrics has published a policy on preventing lead toxicity in children.⁶⁶ They reported that for every US dollar (A$1.34) spent on reducing lead exposure in housing, the benefit would be between US$17 (A$23) and US$221 dollars (A$297), a favourable cost-benefit ratio.^66,67 This policy outlines a number of recommendations largely aimed at primary prevention for both government and health professionals including increasing resources for lead control, continuing research into plumbism and screening.⁶⁶

Management in Adults

The management and prevention of toxicity in adults is similar to that in children. In adults, occupational exposure is an additional aspect. The Therapeutic Guidelines recommend immediate intravenous chelation therapy in adults with lead encephalopathy and oral chelation therapy for symptomatic adults with blood levels >3.4 μmol/L (70 μg/dL).⁶⁴ Kosnett et al. advised that adults with a blood level >1.4 μmol/L (30 μg/dL), or >0.92 μmol/L (20 μg/dL) on two occasions four weeks apart, should be removed from occupational exposure. In those patients who are exposed in their work environments, they advised regular monitoring with intervals varying depending on previous concentrations. Similarly to children, all adults with an elevated blood level should have the source of exposure identified and removed or decreased if removal is not an option.⁶⁸

Despite these clear recommendations for removing the exposure source, mining and smelting continue to occur in contemporary Australia, adversely affecting the health of local residents.

Conclusion

Despite extensive knowledge throughout the ages of the dangers of lead toxicity, we continue to face this problem with historical and contemporary sources of exposure continuing to affect the health of Australians, in particular children and Aboriginal and/or Torres Strait Island peoples. In light of new information about the adverse effects of lead at seemingly low concentrations, detection capability is particularly important with a move towards ICP-MS. Lead affects many physiological systems causing devastating health outcomes. Management advice is variable with chelation therapy recommended at particularly elevated lead levels or in patients with lead encephalopathy. Nutritional assessment, treatment of iron deficiency and prompt identification and removal of the source of exposure is advised. There is dismal evidence that chelation therapy improves developmental outcomes, making primary prevention of lead exposure of paramount importance for both government and health professionals alike.