14.3
Lead
Lead is not required as a trace element in the body. The harmful effects of lead have been recognized for centuries and have even been reported as a contributing factor in the downfall of the Roman Empire. Metallic lead is used in storage batteries, cables, and elec-tronic equipment. Inorganic lead salts are used in the production of pesticides, paint, ceramics, glass, plastic, and rubber products.
Lead does not have any specific historical medicinal usage, although it has been an ingredient in cosmetic products (and is still illegally used in skin-lightening products).
Lead is present in both inorganic and organic forms. Lead has an affinity for bone and acts by replacing calcium. It is deposited in growing bone and will accumulate with repeated exposures. Ingested lead is absorbed more readily by children, which makes children more sensitive to the toxic effects of lead than adults: in children, 40 % of ingest-ed lead is absorbingest-ed, whereas only 5–15 % is absorbingest-ed by adults (HPA 2007 ). Approximately 50–90 % of inhaled lead enters the blood. Children under 3 years are especially vulnerable because they both absorb lead more effectively than adults and usually have greater exposures
Box 14.1 The concept of ‘as low as reasonably practicable’
As low as reasonably practicable
In the case of genotoxic compounds for which we assume no threshold, exposures must be kept ALARP, i.e. ‘as low as reasonably practicable’. The concept of ALARP involves the consideration of the risks and benefits of the exposure, and so this could mean that some exposures to the chemical may not be permitted at all. For example, such compounds would not be used in household products, cosmetics, food additives, and similar products which are frequently used. However, industrial use could be allowed under strictly controlled conditions.
because of their exploratory behaviour and frequent hand-to-mouth activity. As the developing nervous system in children is much more vulnerable to damage than the nerv-ous system in adults, pregnant women are also a high-risk group. Lead follows similar metabolic pathways to calcium in the body, so can pass through the placenta, and infants can also be exposed during lactation.
The toxicology of lead is summarized in the Health Protection Agency (HPA) Compendia of Chemical Hazards Series (HPA 2007 ); the summary of the health effects is given below.
14.3.1 Toxicity of lead
Lead is classically a chronic or cumulative toxic substance. Few adverse health effects are observed following an acute exposure at low dose levels. Acute effects including gastro-intestinal disturbances (loss of appetite, nausea, vomiting, abdominal pain), neurological effects (encephalopathy, malaise, drowsiness), hepatic and renal damage, and hypertension have been reported.
Chronic lead exposure may cause anaemia, basophilic stippling (presence of many blue-staining granules within red blood cells), and decreased haemoglobin synthesis. Neurological effects may also be observed such as fatigue, sleep disturbance, headache, irritability, leth-argy, slurred speech, convulsions, muscle weakness, ataxia, tremors, and paralysis.
Epidemiological studies in children have shown an inverse relationship between blood lead concentrations above 10 μ g/dl and intelligence quotient (IQ). There is some evidence that even lower exposures are also harmful, and it is therefore assumed that there is no completely harmless level of exposure to lead.
Nephropathy (kidney disease) and renal tubule dysfunction (dysfunction in the tubules of the filtering units — nephrons — in the kidney) may arise following chronic lead exposure. Hepatic damage has been reported in a few cases only, following occupational exposure to lead. Gastrointestinal disturbances such as nausea, vomiting, anorexia, constipation, and abdominal cramps have also been observed in workers.
Chronic exposure to lead may cause adverse effects on both male and female reproductive functions. Females may experience spontaneous abortion, stillbirths, or low birth weight Table 14.1 Chelating agents currently recommended for storage by emergency departments for heavy metal poisoning
Antidote Indication
Desferrioxamine Iron
Prussian Blue Thallium
Sodium calcium edetate Heavy metals (particularly lead)
Succimer (DMSA) Heavy metals (particularly lead and arsenic) Unithiol (DMPS) Heavy metals (particularly mercury)
Penicillamine Copper
Data from College of College of Emergency Medicine, Guideline on Antidote Availability for Emergency Departments (May 2008) www.collemergencymed.ac.uk/asp/document.asp?ID=4685
following occupational exposure before or during pregnancy. Males may experience reduced libido and/or have low semen volumes and sperm counts along with a decrease in sperm motility.
Occupational exposure to lead has been reported to cause an increase in sister chromatid exchange and chromosomal aberrations, with worker blood concentrations of 80 μ g/dL.
However, such increases were not observed in environmentally exposed children with blood concentrations between 30 μ g/dL and 63 μ g/dL.
Based on epidemiological and experimental data, the Working Group of the International Agency for Research on Cancer concluded that inorganic lead compounds are probably carcinogenic to humans (Group 2A) (IARC 2006 ).
14.3.2 Regulation of lead
The high toxicity of lead has been recognized for many years and has led to a raft of regu-lation to reduce exposures wherever reasonably practical over the past two decades. The elimination of lead in petrol has been of critical importance, although there are concerns about the resultant increased use of benzene, a recognized carcinogen, to sustain high octane ratings, however legislation (in 2000) reduced the maximum amount of benzene in petrol to 1 % .
Lead is banned in cosmetics manufactured or marketed in the EU (and the UK).
However, cosmetics are sometimes brought into the UK from abroad for personal use or bought via the internet, so should not be ruled out as a possible source of exposure. Lead has recently been found in kohl, a widely used traditional cosmetic mainly worn around the eyes.
Legislation controlling the marketing and use of lead in paint in the UK came into force in 1992 with the Environmental Protection (Controls on Injurious Substances) Regulations.
However, voluntary agreements between the Paintmakers’ Association (now called the British Coatings Federation) and the UK government initially came into being in 1963 (revised in 1974). Under this accord, paints which contained more than 1 % lead in dry film had to be labelled with a warning that they were not to be used on surfaces accessible to children. In practice, however, the UK paint industry had begun to replace its use of white lead (lead carbonate/lead sulphate) in the 1950s with alternatives, such as titanium dioxide, that are technically superior and also considered less hazardous. In the 1960s, lead-drying agents also began to be phased out, along with coloured lead pigments in decorative paints, so that ordinary paints in the UK were virtually lead-free from the 1960s. Some very limited uses of lead did continue, such as in thin primer paints on some prefabricated domestic wooden windows up to the 1980s, and in products intended for professional use. The Lawther Working Party for the then Department of Health and Social Security estimated in its 1980 report that lead-based paints accounted for less than 3 % of the current market.
The occupational use of lead is strictly governed by the Control of Lead at Work Regulations 2002 and the Health and Safety at Work (etc.) Act 1974.
The use of lead water supply pipes is no longer permitted in new dwellings or in repairs to old systems. In areas with a plumbosolvent public water supply (water that is able to
dissolve lead) grants are available from local authorities for the removal of old pipe-work, although these are usually means-tested and therefore of limited impact.
In addition, lead solder may still legally be used in central heating supply pipes and there has been at least one incidence where this has inadvertently been used in pipes for a drinking water supply.
As a result of these efforts, blood-lead levels in the UK have fallen dramatically in recent decades and surveys indicate that the great majority of UK children are now well below the target level for blood-lead of 10 μ g/dl, set by the International Miami Declaration on Children’s Environmental Health, which the UK signed in May 1997.
It is reasonable to expect further reductions in blood-lead levels, as older legislation continues to have an effect and newer actions, such as lowering limits for lead in drinking water, are introduced. However, it is important to note that the 10 μ g/dl level does not denote a concentration at which lead poisoning begins, rather it is a target to minimize the possibility of harm to populations at risk. Indeed recent evidence suggests that some intellectual impairment may occur at levels below 10 μ g/dl. The underlying assumption is that no exposure to lead is completely harmless and the aim is therefore to reduce expo-sure wherever reasonably practicable.
The Housing Act 2004 introduced a new system for rating the ‘fitness’ of housing. The system is used by local authority environmental health practitioners to secure the reme-diation of hazards, including domestic lead exposure, such as from old paintwork and lead water pipes. However, the removal of lead paintwork can itself present hazards — from paint dust and vapours from the use of paint-stripping hot-air guns. Advice on safe removal is given in a DEFRA advice sheet (DEFRA 2005 ).
14.4
Zinc
Zinc salts are used in soldering, cement additives, horticultural chemicals, and dry cells.
Zinc phosphide is used as a rodenticide and zinc is also found in numerous topical skin preparations as zinc oxide.
Zinc is a good example of an essential trace element. It was reviewed by the EVM in their report Safe Upper Levels for Vitamins and Minerals (EVM 2003 ).
Meat and cereals are good sources of zinc in the diet. The Committee on Medical Aspects of Food Nutrition and Policy (COMA) determined a reference nutrient intake (RNI) for zinc. An RNI is the amount of nutrient that is enough or more than enough for most (usually at least 97 % ) people in a group; if the average intake in this group is at the RNI then the risk of deficiency in the group is very small. The RNI for zinc is 5.5–9.5 mg/
day for men and 4.0–7.0 mg/day for women (COMA 1991 ).
Zinc is essential as it is a constituent of more than 200 enzymes and is necessary for cell division. Zinc deficiency is associated with a range of adverse effects, including poor pre-natal development, mental retardation, impaired conduction of nerve impulses, repro-ductive failure, dermatitis (inflammatory disorders of the skin), hair loss, diarrhoea, loss of appetite (anorexia), anaemia, susceptibility to infection, delayed wound healing, and macular degeneration (change in the eye which affects vision).
14.4.1 Toxicity of zinc
Symptoms of acute toxicity caused by over-exposure to zinc include abdominal pain, nausea and vomiting, lethargy, anaemia, and dizziness.
Prolonged use of high doses of zinc can result in secondary deficiency of copper, which gives rise to a wide range of effects. These include hypocupraemia (reduced copper content in the blood) and impaired iron mobilization.
Changes in the blood also occur due to deficiencies in copper, including anaemia, leu-copaenia (decreased white cells in the blood), neutropaenia (a decrease in neutrophils — a specific type of white blood cell), increased plasma cholesterol, and increased low-density lipoprotein to high-density lipoprotein (LDL:HDL) cholesterol ratio. The increase in LDL:HDL ratio is considered harmful as low density lipoproteins are associated with heart attacks, whereas high density lipoproteins are considered protective against heart attacks.
Other toxic effects associated with zinc-related copper deficiency include decreased erythrocyte superoxide dismutase activity, decreased cytochrome C oxidase activity, decreased glucose clearance (decreased removal of glucose in the blood by the kidneys), decreased methionine, decreased leucine enkephalins, abnormal cardiac function, and impairment of the pancreatic enzymes amylase and lipase.
Acute toxicity occurs in humans after oral doses of 200 mg of zinc or more. The most sensitive indicator of zinc toxicity is the reduction in copper absorption, measured through effects on the copper-dependent enzyme erythrocyte superoxide dismutase. Repeated daily exposure to 50 mg for several weeks results in effects on this enzyme and a reduction in haematocrit (the blood test which measures the ratio of volume of cells to volume of plasma) and serum ferritin levels. Doses greater than 100 mg per day have resulted in an altered ratio of LDL:HDL cholesterol. This may be why excess zinc is considered athero-genic, i.e. able to cause the formation of lipid deposits within the lumen of arteries.
The EVM recommend a safe upper level for daily consumption of 25 mg zinc/day for supplemental zinc (EVM 2003 ).
Inhalation of zinc compounds may result in local irritation of the nose and throat, causing shortness of breath (dyspnoea), cough, chest pain, headache, nausea, and vomiting.
Chronic exposure may cause changes in the lung tissues, fibrosis of the lung, or inflam-mation of lungs (pneumonitis).
14.4.1.1 Metal fume fever
Under occupational exposure conditions, inhalation of zinc compounds (mainly zinc oxide fumes) can result in a condition referred to as ‘metal fume fever’. Metal fume fever’s unique symptoms have been described in welders/metal workers since the early 19th century. It is an acute, self-limited syndrome characterized by a delayed onset (4–12 hours) after exposure to welding fumes. Symptoms tend to resolve spontaneously in 24–48 hours and treatment is generally supportive and non-interventional. The precise underlying disorders are not known with certainty, and metal fume fever can occur either following the first exposure to metal fumes or after repeated exposures. There is a tendency for attacks to be worse at the beginning of the working week — hence the popular name Monday Morning Fever (Greenberg et al. 2003 ).
The clinical features of metal fume fever are irritation of the nasal passages, cough, abnormal sounds in the lungs (known as rales) when breathing is heard through a stetho-scope, reduced lung volumes, increased rate of breathing (hyperpnoea), and an alteration in the ability of gases to diffuse across the lung to the blood (as detected by a carbon mon-oxide diffusing capacity test), headache, altered taste, fever, weakness, sweating, pains in legs and chest, and an increase in white blood cells (leukocytosis).
Although metal fume fever occurs in occupationally exposed workers, it is essentially an acute reversible disorder that is unlikely to occur under chronic exposure conditions.
The workplace exposure limit for zinc chloride fumes is 1 mg/m 3 over an 8-hour period (HSE 2005 ).
14.5
Mercury
Mercury has in the past been used as an ingredient in diuretics, antibacterial agents, anti-septic skin ointments, laxatives, and hair-conditioning agents, and was used in dentistry for many centuries. Mercurous (calomel) salts were also historically used as a purgative.
Mercuric salts (e.g. mercuric chloride) were used as disinfectants and because of their high solubility and acute toxicity have been used as homicidal agents.
14.5.1 Forms of mercury 14.5.1.1 Organic mercury
Organomercury compounds such as methyl mercury are a particular environmental con-cern because of their formation through the methylation of inorganic mercury by micro-organisms in aqueous environments. Methyl mercury is accumulated in the aquatic food chain and the mercury concentrations in shellfish or predatory fish (e.g. shark, swordfish) are of particular concern to public health (see Section 3.4 on food contaminants). Organic mercury is readily absorbed through the gastrointestinal system into the systemic circula-tion and readily crosses the blood–brain barrier; it is concentrated in the brain as well as the kidney, liver, hair, and skin. Organic mercury also readily crosses the placenta.
Organic mercury compounds may have significant volatility and may be readily absorbed by inhalation and through the skin as well as orally.
14.5.1.2 Inorganic mercury
When ingested, inorganic mercury salts can be absorbed from the gastrointestinal tract.
However, they are poorly lipid-soluble and only around 10 % of an ingested dose would be absorbed. Once absorbed, inorganic mercury is concentrated in the kidneys. Inorganic mercury compounds do not in general pose a significant risk by the inhalation route as they are not encountered in a respirable form. However, there have been recent reports of the use of mercury-containing skin-lightening creams containing significant quantities of mer-cury being associated with the development of nephrotic syndrome (Choudhury 2011 ).
14.5.1.3 Elemental mercury
Elemental mercury, as present in mercury thermometers, is not absorbed through the intact gastrointestinal tract to any significant extent, nor through the skin. However, elemental
mercury vapour is readily absorbed by inhalation. Mercury can pose a health risk from exposure to modest amounts, such those found in thermometers if spills are not cleaned up effectively.
The toxicology of inorganic and elemental mercury is summarized in the HPA Compendia of Chemical Hazards Series (HPA 2007 ); the summary of the health effects is given below.
14.5.2 Toxicity of mercury
Mercury poisoning may often be misdiagnosed as the symptoms are non-specific and insidious in nature. The gastrointestinal system, the nervous system, and the kidneys are the most common organ systems affected.
Following an acute exposure to elemental mercury vapour via inhalation, respiratory effects such as cough, dyspnoea (shortness of breath), chest tightness, bronchitis, and decreased pulmonary (lung) function may occur. Cognitive, personality, sensory, or motor disturbances may also arise, including tremor, irritability, hallucinations, muscle weakness, and headaches. Because of the accumulation of mercury in the kidneys, acute renal failure indicated by proteinuria (passage of proteins in the urine), haematuria (passage of blood in the urine), and oliguria (passage of reduced amounts or volumes of urine) is commonly reported. Acute inhalation of elemental mercury may also cause gastrointesti-nal effects such as stomatitis (inflammation of the mouth), abdomigastrointesti-nal pain, vomiting, diarrhoea, and ulceration of the oral mucosa, as well as cardiovascular effects such as hypertension (high blood pressure) and tachycardia (increase in heart or pulse rate).
Inorganic mercury compounds are highly irritating to the gastrointestinal tract and an acute ingestion may cause a metallic taste, abdominal pain, vomiting, diarrhoea, and necrosis of the intestinal mucosa, possibly leading to circulatory collapse and death.
Ulceration of the mouth, lips, tongue, and gastrointestinal tract may also occur. If patients survive damage to the gastrointestinal tract, acute renal failure may occur within 24 hours of ingestion. Hypertension and tachycardia have also been reported following ingestion of inorganic mercury compounds.
Acute dermal exposure to elemental mercury vapour can cause erythematous (reddish) and pruritic (itchy) skin rashes, reddening and peeling of skin on palms of feet and hands associated with acrodynia, and contact with soluble inorganic mercury compounds may cause irritation, vesiculation, and contact dermatitis.
Chronic exposure to elemental mercury vapour via inhalation may cause neurotoxicity, resulting in decreased psychomotor skills (skills requiring co-ordinated thinking and muscle activity) and neuropsychological symptoms including fatigue, tremor, headaches, depression, irritability, and hallucinations. Nephrotoxicity (toxicity to the kidney) leading to proteinuria and increased urinary enzyme excretion was observed following occupa-tional exposure to elemental mercury, as well as stomatitis (inflammation of the mouth), sore gums, and ulceration of the oral mucosa.
Chronic ingestion of inorganic mercury compounds may cause irritability, weakness, insomnia (inability to fall asleep), muscle twitching, swollen gums, excess salivation, ano-rexia, and abdominal pain.
There is little convincing evidence that exposure to mercury causes chromosomal damage or other mutagenic effects. The IARC have classified elemental mercury and inorganic mercury compounds as category 3 carcinogens, i.e. not classifiable as to its carcinogenic-ity to humans (IARC 1997a ).
Conflicting evidence regarding the incidence of spontaneous abortion following inorganic mercury exposure has been presented. Some studies have reported a higher incidence of reproductive failures (spontaneous abortions, still births, congenital malformations) and irregular, painful, and haemorrhagic menstrual disorders in occupationally exposed women compared to unexposed women.
14.5.2.1 Toxicity of mercury dental amalgams
The toxicity of mercury from dental amalgams is a contentious issue. The views of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) were first sought on this issue in 1986. At that time, the Committee recognized that some mercury may be released from completed dental restorations but was of the
The toxicity of mercury from dental amalgams is a contentious issue. The views of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT) were first sought on this issue in 1986. At that time, the Committee recognized that some mercury may be released from completed dental restorations but was of the